English
Tiếng Việt
(en)The present invention includes compositions and methods related to the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site on the surface of the influenza A non-structural protein 1 (NS1). Specifically, critical biochemical reagents, conditions for crystallization and NMR analysis, assays, and general processes are described for (i) discovering, designing, and optimizing small molecule inhibitors of influenza A (avian flu) viruses and (ii) creating attenuated influenza virus strains suitable for avian and human flu vaccine development.
1.ApplicationNumber: US-201414313534-A
1.PublishNumber: US-2014308307-A1
2.Date Publish: 20141016
3.Inventor: MONTELIONE GAETANO T.
DAS KALYAN
ARNOLD EDWARD
MA LI-CHUNG
XIAO RONG
KRUG ROBERT M.
TWU KAREN Y.
KUO REI-LIN
4.Inventor Harmonized: MONTELIONE GAETANO T(US)
DAS KALYAN(US)
ARNOLD EDWARD(US)
MA LI-CHUNG(US)
XIAO RONG(US)
KRUG ROBERT M(US)
TWU KAREN Y(US)
KUO REI-LIN(TW)
5.Country: US
6.Claims:
(en)The present invention includes compositions and methods related to the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site on the surface of the influenza A non-structural protein 1 (NS1). Specifically, critical biochemical reagents, conditions for crystallization and NMR analysis, assays, and general processes are described for (i) discovering, designing, and optimizing small molecule inhibitors of influenza A (avian flu) viruses and (ii) creating attenuated influenza virus strains suitable for avian and human flu vaccine development.
7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. Ser. No. 13/907,472, filed on May 31, 2013, which is a divisional patent application of U.S. Ser. No. 12/706,804, filed on Feb. 17, 2010, now U.S. Pat. No. 8,455,621, which is a divisional of U.S. patent application Ser. No. 11/566,216, filed on Dec. 2, 2006, now U.S. Pat. No. 7,709,190, which claims priority to U.S. Provisional Application Ser. No. 60/741,764, filed Dec. 2, 2005 and Ser. No. 60/852,361 filed Oct. 16, 2006. All of the foregoing applications are hereby incorporated by reference in their entirety.
STATEMENT OF FEDERALLY FUNDED RESEARCH
This invention was made with U.S. Government support under Contract Nos. AI-11772 awarded by the NIH. The government has certain rights in this invention.
TECHNICAL FIELD OF THE INVENTION
The present invention relates in general to the field of anti-viral assays and molecules, and more particularly, to compositions and methods for developing, isolating and characterizing novel Influenza A virus inhibitors and vaccines.
INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC
The present application includes a TABLE filed electronically via EFS-Web that includes a file named NS1A_F2F3. The table was last modified Dec. 1, 2006 at 4:49 PM and includes 252,952 bytes.
TABLES
The patent application contains table(s) that have been included at the end of the specification.
BACKGROUND OF THE INVENTION
Without limiting the scope of the invention, its background is described in connection with Influenza virus.
Influenza A and B viruses cause a highly contagious respiratory disease in humans resulting in approximately 36,000 deaths in the United States annually (Wright and Webster, 2001; Prevention, 2005). These annual epidemics also have a large economic impact, and cause more than 100,000 hospitalizations per year in the United States alone. Influenza A viruses, which infect a wide number of avian and mammalian species, are responsible for the periodic widespread epidemics, or pandemics, that have caused high mortality rates (Wright and Webster, 2001). The most devastating pandemic occurred in 1918, which caused an estimated 20 to 40 million deaths worldwide (Reid et al., 2001). Less devastating pandemics occurred in 1957 and 1968. Influenza B virus infections comprise about 20% of the yearly cases, but influenza B virus, which appears to infect only humans, does not cause pandemics (Wright and Webster, 2001).
Influenza A and B viruses contain negative-stranded RNA genomes, which are in the form of eight RNA segments (Lamb and Krug, 2001). Most, but not all, of the corresponding genome RNA segments of influenza A and B viruses encode proteins of similar functions. Here we will focus on influenza A virus. The three largest genome segments encode the three subunits of the polymerase, PB1, PB2 and PA. The segment encoding PB1 also encodes a small nonstructural protein, PB1-F2, which has apoptotic functions. The middle-sized segments encode the hemagglutinin (HA), the nucleocapsid protein (NP) and the neuraminidase (NA). HA, the major surface protein of the virus, binds to sialic acid-containing receptors on host cells, and is the protein against which neutralizing antibodies are produced. NP protein molecules are bound at regular intervals along the entire length of each of the genomic RNAs to form ribonucleoproteins (RNPs), and also have essential functions in viral RNA replication. The NA viral surface protein removes sialic acid from glycoproteins. One of its major functions is to remove sialic acid during virus budding from the cell surface and from the HA and NA of the newly assembled virions, thereby obviating aggregation of the budding virions on the cell surface. The seventh genomic RNA segment encodes two proteins, M1 (matrix protein) and M2. The M1 protein underlies the viral lipid membrane, and is thought to interact with the genomic RNPs and with the inner (cytoplasmic) tails of the surface proteins, e.g., HA and NA. The M2 protein is an ion channel protein that is essential for the uncoating of the virus. The smallest segment encodes two proteins, NS1A and NS2. The NS2 protein mediates the export of newly synthesized viral RNPs from the nucleus to the cytoplasm. The NS1A protein is a multi-functional protein not that is not incorporated into virion particles (hence the designation “non structural”), and is discussed below.
The primary means for controlling influenza virus epidemics has been vaccination directed primarily against HA (Wright and Webster, 2001). However, the antigenic structure of the HA of influenza A virus can undergo two types of change (Wright and Webster, 2001). Antigenic drift results from the selection of mutant viruses that evade antibodies directed against the major antigenic type of the HA circulating in the human population. Mutant viruses are readily generated because the viral RNA polymerase has no proof-reading function. Because of antigenic drift, the vaccine has to be reformulated each year. Antigenic shift in HA results from reassortment of genomic RNA segments between human and avian influenza A virus strains, resulting in a new (potentially pandemic) virus encoding a novel avian-type HA that is immunologically distinct. The human population has little or no immunological protection against such a new virus. The viruses containing the H2 and H3 HA subtypes that caused pandemics in 1957 and 1968, respectively, resulted from the reassortment of avian and human genomic RNA segments (Wright and Webster, 2001). The HA of influenza B viruses undergoes antigenic drift, but not antigenic shift, because influenza B viruses do not have non-human hosts.
Pandemic influenza A viruses can also apparently arise by a different mechanism. It has been postulated that the 1918 H1 pandemic strain derived all eight genomic RNAs from an avian virus, and that this virus then underwent multiple mutations in the process of adapting to mammalian cells (Reid et al., 2004; Taubenberger et al., 2005). H5N1 viruses, which have already spread from Asia to Europe and Africa, appear to be undergoing this route for acquiring pandemic capability (Horimoto and Kawaoka, 2005; Noah and Krug, 2005). These viruses, which have been directly transmitted from chickens to humans, contain only avian genes, and are highly pathogenic in humans. The human mortality rate has been high, approximately 55% (WHO, 2006). H5N1 viruses have not yet acquired the ability for efficient transmission from humans to humans. Recent studies indicate that efficient human transmission will require more than the acquisition of the ability of HA to bind to human sialic acid receptors in the upper respiratory tract of mammalian organisms (Maines et al., 2006). However, at least one H5N1 gene, the PB2 gene, has already undergone adaptation to mammalian cells (Hatta et al., 2001). The vast majority of pathogenic H5N1 viruses have acquired a lysine at position 627 in the PB2 protein, in place of the glutamic acid that is found at this position in avian viruses. The presence of lysine at this position apparently enhances virus replication in mammalian cells, but the mechanism of enhancement has not been established (Crescenzo-Chaigne et al., 2002; Shinya et al., 2004).
Effective control of a H5N1 pandemic will require the use of antiviral drugs because it is not likely that sufficient amounts of an effective vaccine will be available, particularly in the early phase of a fast-spreading pandemic (Ferguson et al., 2005; Longini et al., 2005; Ferguson et al., 2006; Germann et al., 2006). Antivirals can be stockpiled, and if appropriately used, should limit the spread of pandemic influenza virus. The strategies that have been proposed for the use of antivirals to stem a H5N1 pandemic would also be expected to lead to more effective use of antivirals during annual influenza epidemics. Currently, there are two classes of antiviral drugs. One class, amantadine/rimantidine, is directed against the M2 ion channel of influenza A viruses (Pinto et al., 1992; Wang et al., 1993; Chizhmakov et al., 1996). Virus mutants resistant to this class of drugs rapidly emerge (Cox and Subbarao, 1999; Suzuki et al., 2003), and many of the human isolates of H5N1 viruses are already resistant to these drugs (Puthavathana et al., 2005). The other class of drugs is directed at NA, and is effective against both influenza A and B viruses (von Itzstein et al., 1993; Woods et al., 1993; Ryan et al., 1994; Gubareva et al., 1995; Kim et al., 1997; Mendel et al., 1998). However, H5N1 viruses that are partially, or completely, resistant to the NA inhibitor oseltamivir have been reported (de Jong et al., 2005; Le et al., 2005). The emergence of H5N1 viruses to these two classes of antiviral drugs highlights the need for additional antiviral drugs against influenza virus.
SUMMARY OF THE INVENTION
The present invention includes the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site, or “binding epitope”, on the surface of the influenza A non-structural protein 1 (NS1). When referring to influenza A, the protein is referred to herein as NS1A. The NS1 protein of influenza A virus will be designated as the NS1A protein to distinguish it from the NS1 protein encoded by influenza B virus, which will be designated as the NS1B protein. Several fragments of the NS1A protein were identified, from various influenza strains, that provide high-level expression and solubility in E. coli expression systems. The present invention also includes expression systems and protocols for producing large quantities of the previously identified F2F3 fragment of human CPSF30, which binds to the NS1A effector domain (Twu et al., 2006). These fragments of the NS1A protein and of CPSF30 provide high quality NMR spectra, suitable for lead compound optimization. Combining these reagents and information, we have designed a gel filtration assay suitable for characterizing complex formation between NS1A and CPSF30 (or fragments thereof), as well as a fluorescence polarization (FP) assay of NS1A-CPSF30 interactions that is suitable for high throughput screening for lead compounds to develop antiviral drugs. Using these reagents, complexes of the tetrameric complex between the NS1A effector domain and F2F3 were also generated. We have also developed a process for crystallizing this complex. These crystals were used to determine the 3D structure of the NS1A effector domain: F2F3 complex, and to definitively identify for the first time all the NS1A amino acids that comprise a portion of the CPSF30 binding epitope in the NS1A protein. These reagents and structural data, together with specific site-directed mutagenesis data, have allowed us to define a structure-based process for high-throughput screening of inhibitors and lead optimization that will allow development of influenza A antiviral drugs. Also disclosed is a process using these reagents and structural data to develop attenuated strains of influenza A suitable for use as animal (e.g. avian) or human vaccines.
Using the present invention it is possible for antiviral drug(s) to be directed at a viral target that differs from that of currently available influenza antivirals. Novel approaches are important because influenza A viruses, including avian influenza virus, are developing resistance to existing antiviral drugs. The present invention also describes a process for developing vaccines using structural information that has not been previously disclosed. A vaccine using live attenuated strains of influenza A virus is expected to provide better protection than a vaccine using inactivated virus. The present invention may also be used to develop, isolate and characterize antiviral drugs and live attenuated virus vaccine for both seasonal and pandemic influenza virus infections.
More particularly, the present invention includes a complex of the F2F3 fragment of CPSF30 with the portion of the NS 1A protein of influenza A virus comprising amino acid residues 85 to 215 (NS1A (85-215)). The complex can be used in a method of identifying an inhibitor of influenza A virus by preparing a reaction system comprising at least a portion of NS1A of an influenza A virus, the F2F3 fragment of CPSF30, and a candidate compound; and detecting binding between the at least a portion of NS1A and F2F3, wherein reduced binding in the presence of the candidate drug relative to the control is indicative of activity of the compound against influenza virus. Examples of the NS1A fragments are listed in Table 2, and may also include the full length NS1A, and mutations thereof. The skilled artisan will recognize that the NS1A protein fragment may be prepared from other strains of influenza A viruses, e.g., human influenza A virus, a bovine influenza A virus, an equine influenza A virus, a porcine influenza A virus, an avian influenza A virus, an avian H5N1 viral strain.
For use with the present invention, the CPSF30 may be, e.g., a full length CPSF30, F3 zinc-finger doman, an F2F3-F2F3 tandem duplex, an F1F2F3 fragment, a soluble fragment of CPSF30, combinations and mutants thereof. Detection of the binding may be by, e.g., a high throughput screening assay, X-ray crystallography, nuclear magnetic resonance, analytical gel filtration, and combinations thereof. Other methods of detecting the interaction of the NS1A and CPSF30 (or portions thereof) may be, e.g., fluorescence resonance energy transfer, fluorescence polarization, immunofluorescence, chemiluminescence, radioimmunoassays, enzyme linked immunosorbent assays, mass spectrometry, and combinations thereof. For example, fluorescence polarization may use either a fluorescent labeled CPSF30, variant or fragment thereof or a fluorescent labeled NS1A protein, variant or fragments thereof.
The present invention also includes a process for using 3D (three-dimensional) information of the CPSF30 binding epitope on the influenza A virus NS1A protein for identifying inhibitors of an influenza A virus by obtaining concurrently the coordinates for the molecular position of at least a portion of an influenza NS1A protein and at least a portion of a CPSF30 protein and designing a molecule that will fit between the influenza NS1A protein and the CPSF30 protein based on the coordinates. The portion of the NS1A protein and the portion of the CPSF30 protein will generally be selected to provide high quality NMR spectra, e.g., the NS1A (85-215) fragment and the F2F3 fragment may be selected to form a tetrameric complex.
In another example, the NS1A (85-215) fragment and the F2F3 fragment may form a tetrameric complex that is crystallized. Other examples may use an NS1A (85-215) fragment and the F2F3 fragment form a tetrameric complex that is crystallized and is used to determine the 3D structure of the NS1A (85-215):F2F3 complex using X-ray crystallography. The method may also include the step of identifying the NS1A amino acids that constitute the CPSF30 binding portion of the NS1A protein.
Yet another embodiment is a method of designing an inhibitor compound of an influenza A virus based on computational methods, wherein the inhibitor that binds at least one residue within the set of residues corresponds to the structure, using the crystal structure and its coordinates. The design method may be facilitated by using NMR spectra of samples of NS1A protein fragments, NMR spectra of samples of NS1A(85-215) or equivalent constructs thereof. The method may further include the step of optimizing the design of the molecule that fits between the NS1A (85-215) protein and the CPSF30 protein using X-ray crystallography, and synthetic chemistry. The method of designing an inhibitor compound may also include the step of optimizing the design of the molecule that fits between the NS1A(85-215) protein and the CPSF30 protein using X-ray crystallography, NMR, synthetic chemistry and combinations thereof. Another embodiment of method of designing an inhibitor compound may also include, optionally or in combination one or more of the following: modifying the F2F3 structure of CPSF30, or any substructure, based on its conformation bound to NS1A to rationally design one or more small molecule inhibitors; modifying the F2F3 structure of CPSF30, or any substructure, to rationally design one or more small molecule inhibitors based on its conformation bound to NS1A of the F2F3 aromatic rings, the sidechain of residue Lys101, or combinations thereof; modifying the F2F3 structure of CPSF30, or any substructure, to rationally design one or more small molecule inhibitors by virtual screening; using the three-dimensional structure of the NS1A binding pocket to select one or more small molecule inhibitors or using the three-dimensional structure of the NS1A binding pocket to select one or more small molecule inhibitors by virtual screening. Any fragments of, full length, and strains of NS1A, and fragments of, full length, and strains of CPSF30 and combinations thereof may be used in conjunction with the method of designing an inhibitor compound.
Another embodiment of the present invention includes a process for engineering a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interface and combinations thereof. Specific examples of residues at the tetramer interface site include, e.g., F103, L105, M106 and equivalents thereof. Specific examples of residues at the CPSF30-binding epitope include, e.g., M106, K110, 1117, 1119, Q121, D125, V180, G183, G184, W187 and equivalents thereof. The process may further include mutating the double-strand RNA binding epitope.
Another embodiment of the present invention includes an attenuated influenza A virus vaccine that includes one or more of eight viral RNA segments, wherein a viral RNA segment eight has a first mutation that causes a substitution of a first amino acid corresponding to an amino acid of SEQ. ID. NO. 1 at a position F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, or W187; wherein the first mutation decreases the CPSF30 binding ability of the NS1A protein. In one embodiment, at least a second mutation anywhere in the NS1A protein. The vaccine may also include at least second mutation causes a substitution of at least a second amino acid corresponding to an amino acid of SEQ ID NO.: 1 at a position F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, W187 and equivalents thereof. Alternatively, the vaccine may also include at least second mutation with a substitution of at least a second amino acid corresponding to an amino acid of SEQ ID NO.: 1 at a position T5, P31, D34, R35, R38, K41, G45, R46, and T49 at a dsRNA binding epitope and equivalents thereof. Alternatively, the vaccine may also include at least second mutation with at least second mutation causes a substitution of at least a second and third amino acid corresponding to an amino acid of SEQ. ID. NO. 1 at a position T5, P31, D34, R35, R38, K41, G45, R46, and T49 at a dsRNA binding epitope and/or F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, W187 and equivalents thereof. The influenza virus is a may be a cold-adapted influenza virus and will generally be selected to elicit an immune response. Non-limiting examples of influenza virus that may be used to make the attenuated vaccine may be is selected from, e.g., a human influenza A virus, a bovine influenza A virus, an equine influenza A virus, a porcine influenza A virus, an avian influenza A virus, an avian H5N1 viral strain.
The present invention also includes a pharmaceutical composition having a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS 1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interaction site and combinations thereof and a pharmaceutically acceptable carrier or diluent. The vaccine may be used in a method of prophylaxis of a disease condition caused by the influenza virus by administering to a subject in need thereof a therapeutically effective amount of a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interaction site, the dsRNA binding epitope and combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:
FIGS. 1A and 1B are graphs that show the effects on the growth of a recombinant influenza A virus resulting from mutations in its of mutations on NS1A protein that relate to the ability of the NS1A to bind to CPSF30;
FIG. 2 shows NMR spectra of certain NS1A effector domains, demonstrating that such data can be used for structure-function analysis, inhibitor discovery and optimization, and in validating the effects of mutations on the structure of the effector domain;
FIG. 3 shows the results from analytical gel filtrations assays of NS1A (85-215):F3F3 binding;
FIG. 4A shows the X-ray crystal structure of a tetrameric NS1A effector domain and F2F3;
FIG. 4B shows the X-ray crystal structure for the Met106 residue in the core of the tetrameric NS1A (85-215):F2F3 complex;
FIG. 5 shows the X-ray crystal structure for the F2F3 binding epitope on the surface of the NS1A effector domain;
FIG. 6 is a comparison of 3D structures for Udorn and PR8 NS1A effector domains; and
FIG. 7 shows the 3D structure and dimeric beta-sheet interface of the PR8 effector domain, which does not bind F2F3.
DETAILED DESCRIPTION OF THE INVENTION
While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
One of the best clues to a protein's function is its structure. The present invention takes advantage of structure-based bioinformatics platforms in “functional genomics.” The structure-function data obtained from various structural determination may be used the isolation of novel biopharmaceuticals and/or drug targets from gene sequence information with greater efficiency. One way to identify the biochemical and medical function of a gene product is to determine its three-dimensional structure. Although there are numerous examples in which the primary (i.e., linear) structure of a protein has provided key clues to its biochemical function, three dimensional (3D) structure determination is considered to be more definitive at establishing biochemical function and mechanisms underlying these functions.
Protein structure. It is a generally accepted principle of biology that a protein's primary sequence is the main determinant of its tertiary structure. Anfinsen, Science 181:223-230 (1973); Anfinsen and Scheraga, Adv. Prot. Chem. 29:205-300 (1975); and Baldwin, Ann. Rev. Biochem. 44:453-475 (1975). For over a decade, researchers have been studying the theoretical and practical aspects of the folding of recombinant proteins.
Generally, proteins are composed of one or more autonomously-folding units known as domains. Kim, et al., Ann. Rev Biochem. 59:631-660 (1990); Nilsson, et al., Ann. Rev. Microbiol. 45:607-635 (1991). Multi-domain proteins in higher organisms are encoded by genes containing multiple exons and combinatorial shuffling of exons during evolution has produced novel proteins with different domain arrangements having different associated functions. Multi-domain protein may increase the ability of higher organisms to respond to environmental challenges because, via recombinational events, because the genomes may readily add, subtract, or rearrange discrete functionalities within a given protein. Patthy, Cell 41:657-663 (1985); Patthy, Curr. Opin. Struct. Bio. 4:383-392 (1994); and Long, et al., Science 92:12495-12499 (1995).
Interpretation of a protein structure. Several methods have been used to elucidate the 3D structure of a given protein molecule, e.g., X-ray crystallography and Nuclear Magnetic Resonance (NMR).
X-ray crystallography. X-ray crystallography is a technique that directly images molecules. A crystal of the molecule to be visualized is exposed to a collimated beam of monochromatic X-rays and the consequent diffraction pattern is recorded on a photographic film or by a radiation counter. The intensities of the diffraction maxima are then used to construct mathematically the three-dimensional image of the crystal structure. X-rays interact almost exclusively with the electrons in the matter and not the nuclei. The spacing of atoms in a crystal lattice can be determined by measuring the angle and intensities at which a beam of X-rays of a given wave length is diffracted by the electron shells surrounding the atoms. Operationally, there are several steps in X-ray structural analysis. The amount of information obtained depends on the degree of structural order in the sample. Blundell et al. provide an advanced treatment of the principles of protein X-ray crystallography. Blundell, et al., Protein Crystallography, Academic Press (1976), herein incorporated by reference. Likewise, Wyckoff et al. provide a series of articles on the theory and practice of X-ray crystallography. Wyckoff, et al. (Eds.), Methods Enzymol. 114: 330-386 (1985), relevant portions herein incorporated by reference. Important techniques for X-ray crystallography include methods for determining diffraction data phases by a multiple anomalous dispersion (MAD) method (described, for example, in Hendrickson, 1991), particularly using biosynthethic enrichment with seleno-methione (SeMet), and a molecular replacement method (described, for example, in Rossmann, M. G. The molecular replacement method. Acta Cryst. A46, 73-82 (1990).
Nuclear Magnetic Resonance (NMR). A general approach for the analysis of NMR resonance assignments was first outlined by Wuthrich, Wagner and co-workers. Wuthrich, “NMR of proteins and nucleic acids” Wiley, New York, New York (1986); Wuthrich, Science 243:45-50 (1989); Billeter, et al., J. Mol Biol. 155:321-346 (1982), relevant portions of each incorporated herein by reference. For a general review of protein determination in solution by nuclear magnetic resonance spectroscopy, see Wuthrich, Science 243:45-50 (1989); Billeter et al., J. Mol. Biol. 155:321-346 (1982). More recent improvements using multidimensional and triple resonance NMR methods (described, for example, in J. Cavanagh, W. Fairbrother, A. Palmer, and N. Skelton, Protein NMR Specroscopy, Principles and Practice, 2ed Ed, Academic Press, N.Y., 2006, incorporated herein), familiar to someone trained in the art, are elaborations of these basic principles.
As used herein, the terms “CPSF30 binding epitope” or “CPSF binding site” refer to that portion of the NS1 protein of influenza that interacts with one or more zinc fingers of the CPSF30 protein.
As used herein, the terms “NS1A-binding epitope” or “NS1A binding site” refer to that portion of the CPSF30 protein that interacts with the NS1 protein of influenza A.
As used herein, the term “tetramer interface” refers to those portions of the NS1A protein and the CSPF30 protein that interact NS1A:CPSF30 complex, which can be a dimer or tetramer.
As used herein, the terms “double-strand RNA binding site” or “doubled-stranded RNA binding epitope” refer to that portion of the NS1A protein that interacts with double-stranded RNA, e.g., for suppressing host innate immune response. Greater structural details regarding the double-strand RNA binding site is taught by the present co-inventors in PCT/US2003/036,292, “Process for Designing Inhibitors of Influenza Virus Non-Structural Protein 1,” relevant portions incorporated herein by reference and U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference.
As used herein, the term “epitope” refers to a portion of a protein that is capable of interacting with the same or another protein and that can be define by atoms in amino acids in a linear sequence, by atoms in amino acids that are located throughout the protein (or subunits thereof) and that come together in three dimensions to form an interactive structure. The skilled artisan will recognize that an epitope may be a structure such as a “zinc finger,” a portion of a molecular surface between two or more polypeptides that are capable of interacting, and/or a “binding pocket” or “enzymatic pocket” that lead to a function or interaction of the protein.
As used herein, the following nomenclature is used to define the zinc finger domains of the CPSF30 protein that interact NS1A, namely, “F1”, “F2” and “F3” when referring to individual zinc fingers, “F1F2”, “F2F3” when referring to a pair of zinc fingers and “F1F2F3” when referring to the three zinc fingers.
As used herein, the term “rationally design” refers to a series of steps for designing, e.g., initial small molecule inhibitors that may be further refined through medicinal chemistry and/or the selection of inhibitors that can be further modified chemically and that fit the molecular characteristics of a molecule that will meet the design criteria for modifying the interactions between or the activity of NS1A and CPSF30 based fully and/or at least in part on the three dimensional (3D) coordinates described herein.
As used herein, the term “virtual screening” refers to in silico design, using computer software to screen for possible binding ligands from a library of virtual molecules, allowing the characterization and refinement of small molecule inhibitors that will meet the design criteria for modifying the interactions between or the activity of NS1A and CPSF30 based fully and/or at least in part on the three dimensional (3D) coordinates described herein.
As used herein, the term “corresponding positions” refers to amino acids at that are generally in the same spatial location in the three-dimensional structures of homologous protein structures. In one example, a corresponding position is determined by 3D structure alignment using standard techniques known to a person skilled in the art, such as the PRISM program, described by Yang and Hong Yang, A.-S. and Honig, B. (2000) An Integrated Approach to the Analysis of Sequence and Structure. I. Protein Structural Alignment and a Quantitative Measure for Protein Structural Distance. J. Mol. Biol. 301: 665-678; Yang, A.-S. and Honig, B. (2000) An Integrated Approach to the Analysis of Sequence and Structure. III. A Comparative Study of Sequence Conservation in Protein Structural Families Using Multiple Structural Alignments, or the VISTAL program, described by Kolodny, R. and Honig, B. (2006) VISTAL—A New 2D Visualization Tool of Protein 3D Structural Alignments. Bioinformatics 22:2166-2167 (e.g., using the default settings for either), relevant portions incorporated herein by reference. The alignment may include the introduction of gaps in the sequences to be aligned. In the absence of 3D structures for protein pairs, corresponding positions may be identified (until such time that the requisite 3D structures are available) by sequence-based alignment using stardard techniques known to a person skilled in the art, such as a Needleman-Wunsch dynamic programming algorithm (described in Needleman, S. B. and Wunsch, C. D., J Mol Biol. 48: 443-453 (1970), a Gapped BLAST/PSI-BLAST algorithm (described in Altschul, et al Nucl. Acid. Res. 25: 3389-3402 (1997), or a CLUSTAL W/X multiple sequence alignment algoithm (described in Thompson, J. D., Higgins, D. G. and Gibson, T. J. (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position specific gap penalties and weight matrix choice. Nucl. Acid. Res. 22:4673-80 (1994).)(e.g., using the default settings for either relevant portions incorporated herein by reference. Corresponding position alignment(s) may also include the introduction of gaps in the sequences to be aligned.
Further examples of “corresponding positions are taught by the present co-inventors in PCT/US2003/036,292, “Process for Designing Inhibitors of Influenza Virus Non-Structural Protein 1,” relevant portions incorporated herein by reference and U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections”, and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference.
Non-limiting examples of numerous influenza A strains may be used with the present invention including those strains that are readily available or will become available as they emerge in human populations. Examples of influenza A strains for use and analysis with the present invention may include A/Memphis/8/88, A/Chile/1/83, A/Kiev/59/79, A/Udorn/307/72, A/NT/60/68, A/Korea/426/68, A/Great Lakes/0389/65, A/Ann Arbor/6/60, A/Leningrad/13/57, A/Singapore/1/57, A/PR/8/34, A/Vietnam/1203/04, A/HK/483/97, A/South Carolina/1/181918 (the 1918 pandemic virus H1N1 strain), and A/WSN/33. The sequences of these strains are available from GenBank, CDC and viral stock may be available from the American Type Culture Collection, Rockville, Md. or are otherwise publicly available.
As used herein, the term “variant” gene or protein refers to a gene or protein that differs from the wild type gene or protein by way of nucleotide or amino acid substitution(s), addition(s), deletion(s), and combinations thereof. Depending on the context, the term mutant is also used to describe variations from the wild-type sequence that are natural, introduced at random and/or introduced into a gene or protein sequence specifically. Likewise, a fragment is used to describe a fragment of the complete length of the translated polypeptide, whether natural or not. Often, the skilled artisan will design fragments that include or avoid certain amino acid that may affect, e.g., synthesis or cause steric hindrance or other design requirements. When designing alternate peptide constructs with enhanced anti-viral properties, substitutions may be used which modulate one or more properties of the molecule. Variants typically include the exchange of one amino acid for another at one or more sites within the peptide. For example, certain amino acids may be substituted for other amino acids in a peptide structure in order to enhance the interactive binding capacity of the structures. Certain amino acid substitutions can be made in a protein sequence (or its underlying DNA coding sequence) to create a peptide with superior functional characteristics. In particular, those changes that enhance the amphipathic, α-helical nature may be desired.
As used herein, the term “candidate compound” refers to any molecule that may inhibit influenza viral growth. The candidate substance may be a protein or fragment thereof, a small molecule, or even a nucleic acid molecule. Various commercial sources of small molecule libraries meet the basic criteria for useful drugs in an effort to “brute force” the identification of useful candidate compounds. Screening of such libraries, including libraries generated combinatorially (e.g., peptide libraries, aptamer libraries, small molecule libraries), is a rapid and efficient way to screen large number of related (and unrelated) compounds for activity. Combinatorial approaches also lend themselves to rapid evolution of potential drugs by the creation of second, third and fourth generation compounds modeled of active, but otherwise undesirable compounds. Candidate compounds may be screened from large libraries of synthetic or natural compounds. One example of a candidate compound library is an FDA-approved library of compounds that can be used by humans. Synthetic compound libraries are commercially available from a number of companies including Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.) and a rare chemical library is available from Aldrich (Milwaukee, Wis.). Combinatorial libraries are available or can be prepared. Alternatively, libraries of natural candidate compounds in the form of bacterial, fungal, plant and animal extracts are also available from, for example, Pan Laboratories (Bothell, Wash.) or MycoSearch (N.C.), or can be readily prepared by methods well known in the art. Candidate compounds isolated from natural sources, such as animals, bacteria, fungi, plant sources, including leaves and bark, and marine samples may be assayed as candidates for the presence of potentially useful pharmaceutical agents. It will be understood that the pharmaceutical agents to be screened could also be derived or synthesized from chemical compositions or man-made compounds.
The amino acid sequence of the NS1A protein of Influenza A virus, A/Udorn/72:
(SEQ ID NO.: 1)
1
MDPNTVSSFQ VDCFLWHVRK RVADQELGDA PFLDRLRRDQ
KSLRGRGSTL GLDIETATRA
61
GKQIVERILK EESDEALKMT MASVPASRYL TDMTLEEMSR
EWSMLIPKQK VAGPLCIRMD
121
QAIMDKNIIL KANFSVIFDR LETLILLRAF TEEGAIVGEI
SPLPSLPGHT AEDVKNAVGV
181
LIGGLEWNDN TVRVSETLQR FAWRSSNENG RPPLTPKQKR
EMAGTIRSEV.
The anti-viral agents disclosed herein may be used in conjunction with methods to reduce virus growth, infectivity, burden, shed, development of anti-viral resistance, and to enhance the efficacy of traditional anti-viral therapies.
The amino acid sequence of the relevant fragments of human CPSF30 (UniProt id 095639):
(SEQ ID NO.: 13)
1
MQEIIASVDH IKFDLEIAVE QQLGAQPLPF
50
PGMDKSGAAV CEFFLKAACG
51
KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD
100
QCEFLHEYDM TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK IKDCPWYDRG
150
FCKHGPLCRH RHTRRVICVN
151
YLVGFCPEGP SCKFMHPRFE LPMGTTEQPP
200
LPQQTQPPAK QSNNPPLQRS
201
SSLIQLTSQN SSPNQQRTPQ VIGVMQSQNS
250
SAGNRGPRPL EQVTCYKCGE
251
KGHYANRCTK GHLAFLSGQ
The amino acid sequence of the relevant fragments of human CPSF30 discussed in this patent are:
F1 Zn-Finger Domain: residues 41-59;
F2 Zn-Finger Domain: residues 68-86;
F3 Zn-Finger Domain: residues 96-114;
F4 Zn-Finger Domain: residues 124-142;
F5 Zn-Finger Domain: residues 148-166; and
F5 Zn-Finger Domain: residues 243-260.
As used herein F2F2 are residues 61-121 of SEQ ID NO.: 13:
61
SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM
100
TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK I
121
As used herein F1F2F3 are residues 39-121 of SEQ ID NO.: 13:
39
AV CEFFLKAACG
50
51
KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD
100
QCEFLHEYDM TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK
121
The anti-viral properties of the peptides disclosed herein allow them to be included in formulations to inhibit virus growth and proliferation. The purified anti-viral peptides may be used without further modifications or they may be diluted in a pharmaceutically acceptable carrier. The invention may be administered to humans or animals, included in food and pharmaceutical preparations. They anti-viral agents may also be used in medicinal and pharmaceutical products (such as fluid containers, iv. bags, tubing, syringes, etc.), as well as in cosmetic products, hygienic products, cleaning products and cleaning agents, as well as any material to which the peptides could be sprayed on or adhered to wherein the inhibition of virucidal growth on such a material is desired.
The dosage of an anti-viral peptide necessary to prevent viral growth and proliferation depends upon a number of factors including the types of virus that might be present, the environment into which the peptide is being introduced, and the time that the peptide is envisioned to remain in a given area.
As used herein, the phrases “pharmaceutically” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well know in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
The active antiviral agents of the present invention may be formulated into classic pharmaceutical preparations and administered via any common route so long as the target tissue is available via that route. These routes of administration include, e.g., oral, alveolar, nasal, buccal, rectal, vaginal or topical. In particular, use of the anti-viral peptides of the present invention in a condom or diaphragm, optionally in conjunction with a spermicidal or other contraceptive substance, is envisioned. Alternatively, administration may be orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous. The antiviral agent may also be administered parenterally or intraperitoneally. Solutions of the antiviral agent may be compounded into a free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The antiviral agent(s) will generally be provided in a pharmaceutical dosage form suitable for injectable use, e.g., sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For widespread use, the antiviral agents may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The antiviral agents will commonly be provided with a carrier, e.g., a solvent or dispersion medium that may include, e.g., water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper dosage fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, the dosage form will include isotonic agents, e.g., sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Generally, sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that includes the basic dispersion medium and the required other ingredients from those enumerated above. Preparation of sterile powders for injectable solutions maybe prepared by, e.g., vacuum-drying, spray-freezing, freeze-drying or other techniques that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
As used herein, a “pharmaceutically acceptable carrier” refers to solvents, dispersion media, coatings, antibacterial and anti-fungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
For oral administration, the antiviral agent(s) of the present invention may be incorporated with excipients and used in the form of ingestible or non-ingestible mouthwashes and dentifrices. A mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution). Alternatively, the antiviral agent(s) may be incorporated into an antiseptic wash containing sodium borate, glycerin and potassium bicarbonate. The antiviral agent(s) may also be dispersed in dentifrices, e.g., gels, pastes, powders and slurries. The antiviral agent(s) may be added in a therapeutically effective amount to a paste dentifrice that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
The antiviral agent(s) may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric and the like. Salts may also be formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
Upon formulation, the antiviral agent(s) will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. Sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), relevant portions incorporated herein by reference. Some variation in dosage will necessarily occur depending on the condition of the subject being treated for which the skilled artisan will determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
In one embodiment, the vaccine comprises a pharmaceutically acceptable vehicle. The suitable vehicles may be both aqueous and non-aqueous. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption. Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, immunostimulats, immunosuppressants, wetting agents, emulsifying and suspending agents, or any combination thereof.
Examples of suitable adjuvants include, without limitation, incomplete Freund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum, Stimulon® QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.), MPL® (3-0-deacylated monophosphoryl lipid A; Corixa, Hamilton, Mont.), and interleukin-12 (Genetics Institute, Cambridge, Mass.).
A person of the ordinary skill in the art has a sufficient expertise to determine the dosage of the vaccines of the instant invention. Such dosage depends on the pathogenicity of the virus included in the vaccine and on the ability of the antigen to elicit an appropriate immune response. In different embodiments of the invention, a virus vaccine composition of the instant invention may comprise from about 10 2 -10 9 plaque forming units (PFU)/ml, or any range or value therein (e.g., 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , or 10 8 ) where the virus is attenuated. A vaccine composition comprising an inactivated virus can comprise an amount of virus corresponding to about 0.1 to 200 μg of the amino acid sequences of the instant invention per ml, or any range or value therein.
The vaccines of the instant invention can be applied in multiple ways. According to one embodiment of the invention, the intranasal administration is via the mucosal route. The intranasal administration of the vaccine composition can be formulated, for example, in liquid form such as, for example, nose drops, spray, or suitable for inhalation. In other embodiment, the vaccine may be administered as a powder, or a cream, or an emulsion.
In another embodiment, the vaccines of the instant invention are applied by an injection, including, without limitation, intradermal, transdermal, intramuscular, intraperitoneal and intravenous. According to another embodiment of the invention, the administration is oral and the vaccine may be presented, for example, in the form of a tablet or encased in a gelatin capsule or a microcapsule, which simplifies oral application. The production of these forms of administration is within the general knowledge of a technical expert.
As used herein, “detectable labels” refer to compounds and/or elements that can be detected due to their specific functional properties and/or chemical characteristics, the use of which allows the agent to which they are attached to be detected, and/or further quantified if desired, such as, e.g., an enzyme, an antibody, a linker, a radioisotope, an electron dense particle, a magnetic particle or a chromophore. The detectable label may be half of a fluorescence resonance energy transfer (FRET) pair (for FRET variations see, e.g., U.S. Pat. No. 6,593,091, issued to Keys, relevant portions incorporated herein by reference). There are many types of detectable labels, including fluorescent labels, which are easily handled, inexpensive and nontoxic. Another example of a detection method relies on hydrogel-coated donor and acceptor beads providing functional groups for conjugation to biomolecules. AlphaScreen® by Berthold Technologies (Bad Wildbad, Germany)(Rouleau, N., Turcotte, S., Mondou, M. H., Roby, P. & Bosse, R. (2003) J Biomol Screen 8, 191-7.).
The present inventors recognized that certain regions of the NS1A protein can be targeted for the development of antiviral drugs. The NS1A protein is a multi-functional dimeric protein that participates in both protein-RNA and protein-protein interactions (Krug et al., 2003). The effector domain, which comprises the C-terminal two-thirds of the NS1A protein, contains the binding site for the 30-kDa subunit of the cellular cleavage and polyadenylation specificity factor (CPSF30) (Nemeroff et al., 1998; Li et al., 2001). This interaction results in the inhibition of 3′ end processing of all cellular pre-mRNAs in infected cells, and as a consequence the production of mature mRNAs encoding antiviral proteins (such as interferon, IFN) is severely inhibited during infection (Shimizu et al., 1999; Kim et al., 2002; Noah et al., 2003). This inhibition is crucial to viral replication and spread, because influenza A virus, like several other RNA viruses (Yoneyama et al., 2004; Sumpter et al., 2005; Seth et al., 2006), efficiently activates the RIG-I RNA helicase and thereby triggers both the activation of IRF-3 and NF-kB and the synthesis of IFN-beta and other antiviral pre-mRNAs (Geiss et al., 2002; Kim et al., 2002; Siren et al., 2006). A recombinant influenza A/Udorn/72 virus expressing a NS1A protein with a mutated binding epitope for CPSF30 induced high levels of IFN-beta mRNA during infection and was highly attenuated (100-1000-fold) (Noah et al., 2003; Twu et al., 2006). A 61-amino-acid domain of CPSF30, comprising two of its zinc fingers (i.e., the F2F3 fragment), was found to bind efficiently to the NS1A protein (Twu et al., 2006). The expression of the F2F3 domain in cells leads to the inhibition of influenza A virus replication and increased production of IFN-beta mRNA, indicating that F2F3 likely blocks the binding of endogenous CPSF30 to the NS1A protein (Twu et al., 2006). These results validate the binding epitope on NS1A for CPSF30 as a potential target for the development of small molecule antiviral drugs directed against influenza A virus and as a target for engineering strains of virus that can be used as live attenuated vaccines.
Previous studies showed that residues 184-188 in the protein sequence of the NS1A protein are required for functional binding of CPSF30 (Li et al., 2001; Noah et al., 2003). Thus, this region is required for the binding of CPSF30 in vitro (Li et al., 2001), and mutation of amino acids 184-188 in the NS1A protein of a recombinant Udorn virus results in high attenuation coupled with increased synthesis of IFN-beta (Noah et al., 2003). These data demonstrate that this binding epitope is essential for virus replication. As shown by the structural studies described below, the 184-188 region of the NS1A protein sequence constitutes a subset of the CPSF30 binding epitope, observed in the 3D structure of the complex between NS1A effector domain and F2F3 which is disclosed for the first time in this Disclosure.
Studies with the NS1A proteins of H5N1 viruses established that the Met (M) residue at position 106 is required for functional F2F3/CPSF30 binding. We showed that the NS1A protein encoded by a pathogenic H5N1 virus that was transmitted to humans in 1997 (A/HK/483/97; HK97) lacks a binding epitope for CPSF30, whereas the NS1A protein encoded by a pathogenic 2004 H5N1 virus (A/Vietnam/1203/04; VN04) has acquired this binding epitope. We were able to generate a CPSF30 binding epitope in the HK97 NS1A protein by changing two of its amino acids to the corresponding amino acids in the VN04 NS1A protein, specifically by changing I at position 106 to M and L at 103 to F. To determine the effects of these two amino acid changes in the HK97 NS 1A protein during virus infection, a recombinant Udorn virus was generated in which the Udom NS gene was replaced by a HK97 NS gene encoding a NS1A protein with these two mutations (Ud/dmHK97 recombinant). The recombinant virus was then compared to the recombinant Ud virus containing the wild-type HK97 NS gene (Ud/HK97 recombinant). During multiple cycle growth the rate of replication and virus yield of the Ud/dmHK97 recombinant was 100-fold greater than with the Ud/HK97 recombinant virus ( FIG. 1A ), and is thus similar to the Udorn parent virus. During single-cycle growth, the Ud/HK97 virus induced a high level of IFN-beta mRNA production, which was almost completely suppressed in the cells infected by the Ud/dmHK97 virus ( FIG. 1B ). Most importantly, the replication of the Ud/dmHK97 virus was inhibited in F2F3-expressing cells (data not shown), indicating that the dmHK97 NS1A protein binds F2F3 in infected cells. The roles of Phe at 103 and the Met at 106 in the NS1A protein in forming the F2F3/CPSF30 complex is elucidated by the herein disclosed X-ray crystal structure of the NS1A:F2F3 complex, which reveals that amino acids 103 and 106 are required for CPSF30 binding because their hydrophobic interactions stabilize a tetrameric structure of the NS1A:F2F3 complex (see below). It should also be emphasized that essentially all (>98%) of the influenza A viruses (H3N2, H2N2 and H1N1) that have been isolated from humans, including the 1918 H1N1 virus, and include M and F at positions 106 and 103 in their NS1A proteins, respectively, indicating that these two amino acids, which are critical for CPSF30 binding and the resulting suppression of the production of IFN-β mRNA, are conserved in human influenza A viruses. Accordingly, the tetrameric complex described in this disclosure is anticipated to be critical for the CSPF30 binding function of all such human influenza A viruses.
EXAMPLE 1
Process for Discovering, Designing, and Optimizing Small Molecule Inhibitors of Influenza A Viruses, Including H5N1 Viruses
Novel Reagents and Structural Data. To further delineate the interface between F2F3 of CPSF30 and the NS1A protein the inventors determined the three-dimensional (3D) structure of the tetrameric F2F3:NS1A complex. Ninety (90) different constructs (Table 2) were screened in order to find constructs suitable for crystallization and NMR analysis. These variants, summarized in Tables 3 and 4, included 8-11 different full-length or subsequences of NS1A with N-terminal (N-His) and C-terminal (C-His) affinity purification tags, prepared as described in Acton et al., 2005 from influenza A strains A/South Carolina/1/181918 (the 1918 pandemic virusH1N1 strain), HK97 (A/HK/483/97, 1997 Hong Kong), VN04 (A/Vietnam/1203/04, 2005 Vietnam), and Udom (A/Udorn/72), respectively. These were assessed in terms of expression level and solubility (Tables 3 and 4), ability to purify, and biophysical properties, including 2D 15 N- 1 H heteronuclear single quantum coherence correlation spectroscopy (HSQC). Many of these reagents, disclosed for the first time here, are useful for influenza A research purposes and for structural studies. The inventors focused on two specific constructs that provide particularly high expression and solubility, making them especially useful for biochemical and biophysical studies: the C-terminal hexaHis-tagged 85-215 amino acid fragments of the NS1A proteins from (i) influenza A/Udorn/72 (A/Udom) and (ii) the H5N1 strain A/Vietnam/1203/04 (A/VN04). These highly soluble constructs can be produced in tens of milligram per liter quantities, and have been produced with SeMet labeling, for crystallography, and with 15 N-enrichment for NMR studies. Excellent quality HSQC NMR spectra can be obtained for these two constructs in the pH range 5.5 to 6.5 ( FIG. 2 ). Under these conditions, these constructs are of sufficiently good quality to indicate high feasibility for further NMR studies. They are also useful for small molecule screening studies. In addition, the F2F3 fragment of CPSF30 has been cloned into a pET expression vector with a N-terminal hexaHis tag (tag sequences are defined in Acton et al., 2005), produced with uniform 13 C, 15 N enrichment, and complete backbone and sidechain resonance assignments have been determined using standard triple resonance NMR methods (Montelione et al., 1999). These NMR-optimized sample conditions and resonance assignments are useful for small molecule screening, lead optimization, and structure-function studies of F2F3:NS1A interactions.
Because virus studies have used influenza A/Udorn/72 virus to identify CPSF30 binding activity during virus infection CPSF30 (Li et al., 2001; Noah et al., 2003), we have developed an assay for the binding of the NS1A Udorn effector domain to the F2F3 fragment of CPSF30 in vitro, using analytical gel filtration with detection of effluent by simultaneous refractive index and static light scattering measurements. The chromatography system used for this assay is described in Acton et al., 2005, in which it is used for other applications. In these studies, illustrated in FIG. 3 , the NS1A Udorn (85-215) construct elutes as a dimer, with molecular weight of ˜30 kDa. When this effector domain construct is first mixed with the 8.5 kDa F3F3 fragment, the resulting complex elutes with a molecular weight of ˜50 kDa, indicating a stoichiometry of 2 F2F3:2 NS1A effector domains. This gel filtration assay provides a convenient qualitative measure of F2F3 binding by NS1A effector domains.
Suitable samples of NS1A Udorn (85-215); the NS1A-Udorn(85-215):F2F3 complex, and other constructs listed in Table 2 and their complexes with F2F3 and CPSF30-derived constructs, can be produced and assessed using this gel filtration assay. These can then be crystallized for X-ray crystallographic analysis. Initial crystals of the NS1A-Udorn(85-215):F2F3 complex were obtained by high-throughput robotic screening using service facilities available through the Hauptman Woodward Res. Inst. (Buffalo N.Y.) (Luft et al., 2003; Acton et al., 2005). Crystallization optimization was then carried out for the NS1A-Udorn(85-215):F2F3 complex at Rutgers, yielding diffraction quality bi-pyramid crystal of size 0.15×0.15×0.25 mm 3 . Conditions providing crystals, and a description of these crystals, are presented herein below. Three-wavelength Se-Met multiple anomalous diffraction (MAD) (2.3 A resolution) and a complete native (1.95 Å resolution) data sets were collected at X25 beam line at Brookhaven National Laboratories. The structure was solved by MAD techniques (Hendrickson, 1991) and refined to 1.95 Å resolution, and is currently refined to a R factor of 0.225 and R free of 0.245, respectively.
Crystallization of NS1A Udorn (85-215):F2F3 Complex. Initial crystallization conditions for NS1A Udorn (85-215):F2F3 complex were obtained by using robotic crystallization facility at the Buffalo facility described above. The most promising condition use 1.77 M potassium nitrate (KNO 3 ) at pH 5.0 as precipitant. This initial crystallization condition was optimized manually at Rutgers. Good quality crystals were obtained using 0.25-1.0 M KNO 3 and 10-20% sucrose/glucose as precipitant at pH 5-6. Diffraction quality crystals were obtained when P94S mutant F2F3 was used in the complex, though similar conditions are expected to provide crystals of the complex with the wild-type (P94) F2F3 sequence. The NS1A Udorn (85-215):F2F3 complex was crystallized with the symmetry of the space group P4 1 with cell parameters a=b=50.96, c=205.39 Å and α=β=γ=90°. A variant used in the X-ray crystal structure determination of NS1(85-215):F2F3 complex has Ser in place of Pro at position 94.
FIGS. 4A and 4B disclose the crystal structure of the Udorn NS1A effector domain (residues 85-215) bound to the F2F3 fragment of CPSF30. Consistent with gel filtration data, the complex forms a tetrameric complex, in which two F2F3 molecules bridge two NS1A effector domains. The structure reveals for the first time the novel spatial arrangement of the subunits in the 2 NS1A: 2 F2F3 complex. This tetrameric arrangement was completely unexpected and novel.
Key residues Met106/Met106′ of NS1A are packed in the core of the tetrameric interface or “tetramerization epitope,” explaining its critical role in CPSF30 binding, as discussed above. However, while Met 106/Met106′ are at the core of the tetrameric complex, they are not part of the primary F2F3/CPSF30 binding pocket. FIG. 5 illustrates the F2F3 binding pocket on the surface the Udorn NS1A effector domain. Specific interactions in this primary binding pocket involve residues K110, 1117, 1119, Q121, V180, G183, G184, and W187 of NS1A and residues F97, F98, F103, and K110 of the F3 finger of CPSF30. It should be noted that these residues include not only amino acids in, or adjacent to, the 184-188 sequence previously identified as part of the CPSF30 binding epitope by mutagenesis studies, but also amino acids in other regions in the NS1A protein not previously recognized to be essential for CPSF30 binding. Mutation of residues G183 or G184 in NS1A(85-215) each to Arg or Asp disrupts or reduces F2F2 binding affinity and/or tetramer formation, based on analytical gel filtration measurements without significantly disrupting the native structure of NS1A(85-215) indicated by 15 N- 1 H HSQC NMR spectra (data not shown), demonstrating a functional role of these sites within the CPSF30 binding epitope of NS1A. Recombinant Udorn viruses encoding NS1A proteins in which either G184 or W187 was changed to Arg are attenuated (data not shown), further demonstrating that these amino acids are required for virus replication. The eight residues in the CPSF30-binding epitope of NS1A ( FIG. 5 ) are almost 100% conserved amongst influenza A viruses isolated from humans (Macken et al., 2001), except for Ile117 which is frequently replaced by Met. Based on this structure, disclosed for the first time here, we propose disruption of 2NS1A:2F2F3 tetramerization as a strategy to inhibit influenza A virus in human. Based on our structural data, we further propose that a small molecule inhibitor that binds tightly to the above described conserved epitope and surrounding regions will disrupt CPSF30 binding and will inhibit influenza A virus in humans. This pocket on the surface of the NS1A effector domain is the target of our proposed drug discovery process.
Table 1 describes some of the specific location of the epitopes described herein as the tetramerization, RNA binding and CPSF30 binding epitopes of NS1A.
TABLE 1
Tetramerization, RNA binding and CPSF30 binding epitopes of NS1A.
NS1A
Interacting
amino
amino acids of
acids
F2F3
Remark
F103
L72, Y88,
F103 contributes to both the tetramer interface and the CPSF30-
M93, P111
binding epitope F103 interacts with F2 and F3 domains of CPSF30,
may play a role in defining angle between F2 and F3 appropriately;
mutation of 103 could affect an intermolecular salt bridge between R73
and D125.
L105
P111, F112,
L105 contributes to both the tetramer interface and the CPSF30-
M124 (NS1A-
binding epitope Adjacent to F103 and also interacting at the tetramer
2)
interface with a 2 nd NS1A molecule.
M106
N107
M106 contributes to both the tetramer interface and the CPSF30-
binding epitope. M106I mutation would effect the positioning of N107
(of F2F3) and/or Q121 (NS1A same molecule) involved in F2F3-
NS1A H-bonds.
K110
K110
K110 contributes to the CPSF30-binding epitope. K110 has H-bond
with the main-chain carbonyl of K101 of F2F3.
I117
F102
I117 contributes to the CPSF30-binding epitope. Part of the
hydrophobic pocket that binds F3
I119
F98, F102
I119 contributes to the CPSF30-binding epitope. Part of the
hydrophobic pocket that binds F3
Q121
S105, S106
Q121 contributes to the CPSF30-binding epitope. H-bond with amino
group of S106 and O γ of 105 (both from CPSF30)
D125
R73
D125 contributes to the CPSF30-binding epitope. Salt bridge with
R73 (of CPSF30)
L144
No inter-
L144 is buried into the hydrophobic core of NS1A that probably
molecular
defines the fold of the protein. A mutation of L144 may alter the shape
interaction
of NS1A, resulting in reduced CPSF30 and/or dsRNA binding
activities
V180
Y97, K101,
V180 contributes to the CPSF30-binding epitope. Part of the F3-
F102
binding pocket.
G183
Y97
G183 contributes to the CPSF30-binding epitope. Part of a helix that
forms a wall of the F3-binding pocket. A side-chain may affect
(enhance or disrupt) the binding of F3.
G184
Y97, F98
G184 contributes to the CPSF30-binding epitope. Part of a helix that
forms a wall of the F3-binding pocket. Positioned between Y97 and
F98 side chains. A mutation of G184 would alter the shape of the
pocket and can severely affect the binding of F3.
W187
C96, Y97, F98,
W187 contributes to the CPSF30-binding epitope. Participates in the
F112
pocket formation.
Recently, the crystal structure of the NS lA effector domain (residues 79 to 205) of the influenza A/PR8/34 (PR8) virus strain was reported (Bornholdt and Prasad, 2006). This PR8 influenza strain is adapted for passage in mouse, presumably as a result of mouse adaptation, the PR8 NS gene attenuates virus growth in mammalian cells in tissue culture (Ozaki et al, 2004). The PR8 NS1A protein does not bind F2F3 because it lacks the consensus human sequence at positions 106 (I instead of M) and 103 (S instead of F) (Macken et al, 2001), therefore we can determine if the attenuation of growth in mammalian cells is caused primarily by the changed amino acids at positions 106 and 103 in the PR8 NS1A protein (data not shown). The absence of a CPSF30 binding epitope in the PR8 NS1A protein presumably resulted from the large number of passages in mice that have adapted the virus for replication in mice. Consequently, the 3D structure of effector domain of the PR8 NS1A protein (Bornholdt and Prasad, 2006) is not suitable for structure-based drug discovery efforts. In addition, its structure may differ from that of a NS1A protein containing a functional CPSF30 binding epitope. Indeed, the 3D structures of the Udorn effector domain monomers in our complex are similar to, but not identical with, the structure of the monomers of the PR8 NS1A effector domain structure ( FIG. 6 ). The PR8 NS1A structure does not have a F2F3-binding epitope like that observed in the 3D structure of the Udorn NS1A structure described herein. In particular, the PR8 NS1A structures lack the hydrophobic pocket that binds F2F3 in the NS1A:F2F3 complex. Moreover, the dimeric interface in crystal structure of the PR8 NS1A effector domain has an intermolecular beta-sheet interaction ( FIG. 7 ) that is completely different from the interface in the crystal structure of the Udorn NS1A effector domain bound to F2F3. Therefore, the dimer of the effector domain of the PR8 NS1A protein is not relevant for the binding of CPSF 30 and to our proposed drug-design strategy.
Fluorescence polarization (FP) assay. Fluorescence polarization (FP) is a spectroscopic method that measures the rotational rate of a sample in solution. It applies polarized light to excite a fluorophore and measures the polarization characteristics of the emitted light (Nasir and Jolley, 1999; Roehrl et al., 2004b). If the sample tumbles slowly compared to the lifetime of the fluorescence, the emitted light retains some of the incident polarization. However, if the sample tumbles fast, the emitted light is isotropic. Therefore, the degree of anisotropy (polarization) of the fluorescent light emitted from a sample provides a measure of the fluorophore's rotational correlation time in the bound state. Given appropriate bound-state lifetimes, rotational correlation times, and changes in rotational correlation upon complex formation, FP assays can be used to measure binding affinities and to screen for binding inhibitors (Schade et al., 1996; Seethala and Menzel, 1998; Roehrl et al., 2004a).
FP with fluorescently-labeled F2F3. A FP assay of F2F3 binding by NS1A is being implemented. As mentioned above, complex formation between F2F3 and various effector domain constructs is observed in gel filtration studies (see FIG. 3 ), indicating a dissociation constant K d tighter than low micromolar. These data of FIG. 3 demonstrate the feasibility of implementing a FP assay for detecting NS1A:F2F3 binding. Moreover, excellent HSQC spectra and essentially complete NMR resonance assignments are available for the F2F3 construct (data not shown); these will be used to assess the native structural integrity of fluorescently-labeled CPSF30 fragments.
In one embodiment of the invention, we will generate a fluorescein (or other fluorophore)—labeled F2F3 (Fluo-F2F3) substrate for FP assay. The F2F3 sequence of human CPSF30 contains 7 Lys and 6 Cys residues, and fluorophore labeling requires careful consideration to ensure proper folding with Zn ligation by these six Cys residues. Two primary strategies will be pursued for labeling F2F3: (i) chemical synthesis with a fluorophore label and (ii) synthesis or biosynthesis of an analog suitable for specific labeling. The 61-residue F2F3 is sufficiently short to allow fluorophore labeling by solid phase peptide synthesis (for example, by a commercial supplier, such as New England Peptide, Inc. Gardner, Mass.). The crystal structure of F2F3 bound to the NS1A effector domain indicates that the N-terminal region is not involved in key binding interactions, and suggests that it may be possible to generate shorter constructs with similar binding affinities.
Those constructs that show tight binding can be synthesized in 100 mg amounts and assayed for structural integrity by 15 N- 1 H HSQC NMR analysis at natural isotopic abundance using a 800 MHz NMR system with cryoprobe.
If for some reason this approach is not successful, fluorophone-labeled F2F3 will be produced by overexpression with a ‘flash’ peptide sequence tag (Griffin et al., 1998; Griffin et al., 2000; Abrams, 2002). When the tetra-cysteine tag [NH 2 -Cys-Cys-Pro-Gly-Cys-Cys . . . ] is incorporated into proteins/peptides it can be specifically conjugated to a biarsenyl-fluorophore ligand (sold by Invitrogen as their Lumio-technology). The modification can even specifically label the tetra-cysteine tag in vivo (Griffin et al., 2000), and thus should not react with any of the six cysteine residues on F2F3. If even both of these approaches prove to be problematic for this tandem Zn-finger domain, alternative strategies for fluorophore labeling are available, such as the method of Ting and colleagues (Chen and Ting, 2005) that utilizes biotin ligase together with appropriate cofactors to introduce fluorescein in a short N-terminal acceptor peptide lacking any Cys residues, allowing the fluorophore to be introduced subsequent to forming the Zn fingers.
Using any of the above labeling approaches, or other possible approaches, the labeled F2F3 can then be folded with Zn ligation using the same protocol we have developed for unlabeled F2F3. In exploring each of these approaches, we will verify that the fluorophore in the N-terminal tag becomes sufficiently immobilized in the complex to provide a significant change in fluorescence anisotropy. If required, a more immobilized Cys residue within the F2F3 sequence with be introduced without interfering with Zn-finger formation, using our 3D structure of the NS1A (85-215):F2F3 complex as a guide. Using one of these labeling routes, or any approach for introducing the fluorescence tag, the resulting FP assay will be validated by measuring competition with unlabeled F2F3.
The crystal structure of the complex between NS1A Udorn(85-215) and the F2F3 CPSF30 reveals that most of the intermolecular interactions between NS1A and F2F3 involve the F3 Zn-finger domain ( FIG. 5 ). Accordingly, a smaller flourescein-labeled F3 finger (Fluo-F3), with ˜4 kDa molecular weight, may have preferential properties in developing a FP assay. Though the binding of the NS1A effector domain to Fluo-F3 is likely to be somewhat weaker than the binding to F2F3, the change in rotational correlation time, and thus the signal-to-noise of the FP assay, will be significantly higher using Fluo-F3 than using Fluo-F2F3. These design principles may be advantageous in development of a high throughput FP assay useful in screening for inhibitors of CPSF30 (or variants, mutants, or fragments thereof) binding to NS1A (or variants, mutants, or fragments thereof).
The crystal structure of the complex between NS1A Udorn (85-215) and the F2F3 fragment further suggests that a tandem repeat of the F2F3 fragment, connected by a short flexible linker, F2F3-F2F3, could also bind in a manner similar to the two independent F2F3 molecules, though potentially with much tighter binding affinity. Accordingly, we will generate a variety of F2F3-F2F3 constructs, as outlined below, assay their binding, and assess the oligomerization states of these complexes by gel filtration with light scattering detection. If indeed a tandem repeat F2F3-F2F3 construct can be generated with even tighter binding than F2F3 itself, it will be used in a more sensitive FP assay, capable of detecting only more tightly-binding inhibitors.
The magnitude of the change in fluorescence anisotropy, which determines the signal-to-noise of the FP assay, depends on the change in rotational correlation time of the fluorophore upon complex formation. If required to enhance this change in rotational correlation time, the relative size of the NS1A component of NS1A:CSPF30 (or fragments thereof) complexes described above can be further increased by expression as a larger fusion protein (e.g., fused to maltose binding protein), or by attachment to beads or microscopic particles using, for example, already available constructs of Tables 2, 3, and 4 with either N- or C-terminal hexHis tags, or using other affinity tags.
EXAMPLE 2
Constructs to be Used in Developing Fluorescence Polarization Assay
The crystal structure of the complex between NS1A Udorn (85-215) and the F2F3 fragment was examined to identify potential linking sites so that the C-terminus of one segment of F2F3 (or portion thereof) would have a favorable path for linking to the N-terminus of the second segment. Considerations for favorable linking geometry include the distance between termini to be linked, the path the linker would need to take, and linker composition and length. A common peptide linker composition used for connecting domains in engineered proteins is some combination of Gly and Ser residues, allowing for conformational flexibility and solubility while remaining somewhat neutral in chemical content, e.g. -Gly-Ser-, or -Gly-Ser-Gly, etc.
Constructs were designed based on the crystal structure of the influenza virus NS1A-CTD protein complex with the F2F3 fragment from the human CPSF30 protein, disclosed for this first time in this Disclosure. The expectation is that a single-chain construct of the F2F3 binding regions observed in the crystal structure would bind more tightly to the NS1A dimer than the separate domains, and might have significant antiviral activity.
The structure was examined to identify potential linking sites so that the C-terminus of one segment of F2F3 (or portion thereof) would have a favorable path for linking to the N-terminus of the second segment. Considerations for favorable linking geometry include the distance between termini to be linked, the path the linker would need to take, and linker composition and length. A common peptide linker composition used for connecting domains in engineered proteins is some combination of Gly and Ser residues, allowing for conformational flexibility and solubility while remaining somewhat neutral in chemical content, e.g. -Gly-Ser-, or -Gly-Ser-Gly, etc.
The sequence of CPSF30 F2F3 used for the specific designs is that used in the crystal structure determination, but amino acid replacements can be considered. The N-terminal portion might include a hexa-His or other tag for convenient purification; alternatively a tag might be encoded at the C-terminus of the construct. Other purification tags may be preferable to oligo-His owing to potential interference with the chelation of zinc ions by the F2 and F3 “Zn finger” segments, which is required for the integrity of the three-dimensional structure and for effective binding to NS1A. In all of these F2F3 sequences, residue Pro92 may be substituted by Ser.
The constructs involving single F3 domains (“one finger”) as opposed to F2F3 domains (“two fingers”) are potentially valuable as minimal/miniature versions because the interaction between separate F2F3 chains in the dimer (chains F2F3-A and F2F3-B) is mediated entirely by residues in F3 and does not involve any residues from F2. The F3 domain itself, or variants, could be used as an antiviral drug.
Relatively few of the residues in F2 make important interactions with the NS1A protein in the dimer of dimers; notable exceptions are Leu72 and Arg73, whose side chains interact extensively with NS1A. The Leu72 and Arg73 interactions could be maintained by a strategic linkage of a Leu-Arg or Arg-Leu peptide to Thr91 (proposed N-terminus of the F3 domain construct). L72-T91 distance is 14.2 A; R73-T91 distance is 17.6 A. Possible extensions to the one-finger F3 domain construct would be Leu-Arg-GSGSG-F3 or Arg-Leu-GSGSG-F3 (see proposed constructs 5a and 5b).
F2F3 sequence (numbered as in human CPSF30 protein):
(SEQ ID NO.: 2)
61 71 81 91
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHIDPESK I
Construct 1. F3-F3: Single F3-linker-F3 construct (tandem F3 construct)(abbreviated: (91-116)-linker(11+)-(91-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Thr91 Ca is 33.3 A; linker can be 10+ flexible amino acids;
11: -
(SEQ ID NO.: 3)
GSGSGSGSGSG- also written as -(GS) 5 G-;
13: -
(SEQ ID NO.: 4)
GSGSGSGSGSGSG- also written as -(GS) 6 G-;
(SEQ ID NO.: 5)
91 101 111 linker
116
TKM P ECYFYS KFGECSNKEC PFLHID -(GS) N G -
91 101 111
TKM P ECYFYS KFGECSNKEC PFLHID
C-terminal residue of tandem construct can be D116 or any extension up to 1121; crystal structure extends only to P117 in one copy and E118 in the other. Both N- and C-termini can have extensions including hexaHis and other tags for convenient purification as discussed in the text.
Construct 2. F2F3-F3: Same as previous construct except that the N-terminal portion of the construct encompasses entire F2F3 segment (abbreviated) (60-116)-linker(11+)-(91-116):
(SEQ ID NO.: 6)
61 71 81 91
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHID -
linker 91 101 111 116
(GS) N G - TKM P ECYFYS KFGECSNKEC PFLHID
Construct 3. F2F3-F2F3: F2F3-linker-F2F3 construct (tandem F2F3 construct)(abbreviated: (60-116)-linker(15+)-(62-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Gly62 Ca is 51.1 Å; linker should be 14+ flexible amino acids:
15: -
(SEQ ID NO.: 7)
GSGSGSGSGSGSGSG- also written as -(GS) 7 G-;
17: -
(SEQ ID NO.: 8)
GSGSGSGSGSGSGSGSG- also written as -(GS) 8 G-;
(SEQ ID NO.: 9)
61 71 81 91 101
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
111
KFGECSNKEC PFLHID -
linker 62 71 81
(GS) N G - GEKTVVCKH WLRGLCKKGD QCEFLHEYDM
91 101 111
TKM P ECYFYS KFGECSNKEC PFLHID.
Construct 4. F3 -F2F3: F3 -linker-F2F3 construct (abbreviated: (91-116)-linker(15+)-(62-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Gly62 Ca is 51.1 Å; linker should be 14+ flexible amino acids.
(SEQ ID NO.: 10)
91 101 111 116 linker
TKM P ECYFYS KFGECSNKEC PFLHID - (GS) N G -
62 71 81 91
GEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHID
Construct 5. XF3-F3: Extended F3-linker-F3 construct. Linker 1 will link a Leu-Arg or Arg-Leu dipeptide to the one-finger F3 domain in a mode to incorporate the important L72 and R73 side-chain interactions from F2 that are otherwise missing. Linker 2 can be 10+ flexible amino acids:
Construct 5a (abbreviated: Leu-Arg-linker(5+)-(91-116)-linker(11+)-(91-116)):
(SEQ ID NO.: 11)
72 73 linker 1 91 101
Leu-Arg - GSGSG - TKM P ECYFYS KFGECSNKEC
111 116 linker 2
PFLHID - (GS) N G -
91 101 111 116
TKM P ECYFYS KFGECSNKEC PFLHID
Construct 5b (abbreviated: Arg-Leu-linker(5+)-(91-116)-linker(11+)-(91-116)):
(SEQ ID NO.: 12)
73 72 linker 1 91 101
Arg-Leu - GSGSG - TKM P ECYFYS KFGECSNKEC
111 116 linker 2
PFLHID - (GS) N G -
91 101 111 116
TKM P ECYFYS KFGECSNKEC PFLHID
Each of the constructs 1-5b above, and variants thereof, will inhibit CPSF30 binding by NS1A, and can potentially be used as lead compounds for drug development and/or as antiviral drugs useful in preventing or treating influenza A infection in humans, poultry (e.g. chicken), and other animals.
Structure-based Lead Optimization using X-ray Crystallography and NMR. The sample preparation and structural characterization of NS1A effector domains from multiple influenza strains, allow the use of both NMR and X-ray crystallography in hit validation, lead compound optimization, and drug discovery.
Crystallography for lead optimization. X-ray analysis has historically been very important to structure-based inhibitor design. Compounds identified as inhibitor “hits” by kinetic assays can be used to form complexes with the target protein. X-ray analysis will reveal the mode of inhibitor binding and act as a basis for further inhibitor design. Crystal inhibitor complexes can also be formed by soaking inhibitors into preformed crystals, or complexes may be grown by co-crystallization. The latter case may be necessary if the complex triggers conformational changes. In either case, diffraction data is collected on a rotating anode source, processed, and converted to electron density maps. The orientation and occupancy of the inhibitors will be observed and compared with binding modes predicted from virtua 1 screening or models from earlier design cycles. In this way, inhibitors analyzed in one cycle of design will feed into subsequent rounds of structural analysis and re-design in the general process of structure-based drug design (Kuhn 2002; Scapin 2006)
Cocrystallization and Crystal soaks. Using crystallization conditions that we have already optimized for the NS1A effector domains, described above, cocrystallizations and crystal soaks can be carried out with lead compounds identified in our high throughput screening efforts. Trials will be carried out to crystallize NS1A effector domain:lead compound complexes. Diffraction data can be collected using either home or synchrotron X-ray sources and the resulting difference electron density maps and 3D structures can be used to characterize small molecule binding epitopes and bound-state conformations. These data can be used screening for lead compounds either one at a time or in high throughput format, lead compound validation, and optimization of lead compounds, using methods familiar to a person skilled in the art.
NMR for lead identification optimization. NMR is also a powerful method for validating intermolecular interactions, and is used extensively in commercial pharmaceutical drug discovery efforts to identify lead compounds and their protein binding sites (Shuker et al., 1996; Hajduk et al., 1997; Moore, 1999a, 1999b; Muegge et al., 1999; Moy et al., 2001; Powers, 2002; Lepre et al., 2004; Rush and Powers, 2004; Mercier et al., 2006; Petros et al., 2006). NMR chemical shift perturbations, of either the protein or the ligand, can be used for screening for small molecule lead compounds, validating initial small molecule hits identified with htp or virtual screening assays, locating the corresponding binding site in the 3D protein structure, and to guide rational lead optimization. NMR methods uniquely complement crystallography studies. Strengths of NMR analysis methods include (i) the ability to detect even weak (k d up to ˜500 micromolar) binding interactions, (ii) compatibility with systems that undergo structural changes upon ligand binding which may not be accommodated by a crystalline lattice, (iii) the ability to adjust solvent conditions over a wide range, and (iv) high sensitivity and very low sample requirements.
Using NS1A effector domain constructs that have already been shown to provide high quality HSQC spectra (e.g., FIG. 2 ), NMR chemical shift perturbation can be used to validate initial small molecule hits identified with high-throughput (htp) or virtual screening assays, locating the corresponding binding site in the 3D protein structure, and for rational lead optimization. Hits identified in htp FP assays will be characterized by assessing perturbations in HSQC spectra for which resonance assignments will be available, and interpreting these effects on the available 3D structures of NS1 effector domains. Some methods suitable for lead compound screening, identification, and optimization envisioned for use with our invention are summarized in C. A. Lepre, J. M, Moore, and J. W. Peng, Theory and Applications of NMR-based Screening in Pharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)), which is incorporated herein by reference. The NMR infrastructure required for such work are available at most large research institutions, including by not limited to Rutgers University, and include 5 mm 600 and 800 MHz NMR cryoprobe systems, as well as a 1 mm 600 MHz NMR equipped with an automated sample changer. The cryoprobes enable recording of high-quality HSQC data using 150 microliter samples at protein concentrations as low as 10 micromolar, and the 1 mm NMR probe provides high quality HSQC data on 7 microliter samples at 100 micromolar concentrations. Such NMR technologies allow NMR screening for lead compound optimization with as little as ˜500 nanomoles of each sample. Where appropriate, the 3D structures of tightly bound small molecule lead compounds may also be determined by NMR methods if they cannot be solved by crystallographic methods. These data will be used in redesign and lead optimization as outlined for crystallographic data above.
Expressed soluble constructs of NS1A outlined in Tables 2, 3 and 4, or their variants, can also be used to screen for small molecule lead compounds using NMR detection of resonances of the small molecule, using limits desribed by (but not limited to) C. A. Lepre, J. M. Moore, and J. W. Peng, Theory and Applications of NMR-based Screening in Pharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)).
Where appropriate, the 3D structures of tightly bound small molecule lead compounds may also be determined by NMR methods if they cannot be solved by crystallographic methods. These data will be used in redesign and lead optimization using synthetic chemistry, as outlined for crystallographic data above.
Antiviral assays. Having identified inhibitors of the interaction between NS1A and CPSF30, the inhibitors would be tested for their ability to inhibit influenza A virus replication in tissue culture studies. Plaque reduction assays in MDCK cells will be used to assay compounds for their ability to inhibit influenza A virus replication (Twu et al., 2006). Monolayers of MDCK cells will be infected with approximately 100 plaque-forming units (PFU) of influenza A/Udorn/72 virus, and after virus adsorption the cells will be overlaid with agar containing a concentration of a compound ranging from 0.001 micrograms/ml to 10 micrograms/ml. Plaques will be counted in duplicate plates and compared to the number of plaques in controls not exposed to the chemical. In parallel cytotoxicity evaluations of lead compounds would be carried out on MDCK cells using the Roche reagent WST-1 (Berridge et al., 2005). The rate of WST-1 cleavage by mitochondrial dehydrogenases, yielding a product with absorbance at 450 nm, correlates with the number of viable cells. These assays will be carried out in 96-well tissue culture plates, and cell viability will be assayed by determining absorbance at 450nm using an ELISA plate reader. Once the most promising lead compounds with low cytotoxicity in both MDCK and human (A549) cells have been identified, we will determine the effect of several concentrations of the compounds on the rate and extent of virus replication during multiple-cycle growth in MDCK cells. The compounds with the greatest inhibitory activity at the lowest concentrations will be used for subsequent studies in a suitable animal model (ferrets).
Applications of NS1A:CPSF30 Inhibitors. These inhibitors can be developed into antiviral drugs that will be effective in the control of influenza virus epidemics and pandemics in humans. Because there is the potential for such epidemics to be man-made, i.e., using influenza A virus as a bioterrorist weapon, such antivirals would also be crucial in this situation. Influenza antiviral drugs will also be important for the control of influenza A infections in commercial poultry stocks, such as chickens.
TABLE 2
pET-based vectors for NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
Full-length
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
1-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
73-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
85-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
91-215
C-His
Not attempted
C-His
C-His
1-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
85-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
73-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
91-211
C-His
Not attempted
Not attempted
Not attempted
85-204
C-His
C-His
C-His
C-His
91-204
C-His
Not attempted
C-His
C-His
TABLE 3
N-terminal His tag NS1 Expression/Solubility results for
NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
FL
yes/low
yes/low
no/na
yes/low
1-215
yes/low
yes/low
yes/no
yes/low
73-215
yes/no
yes/med
yes/no
yes/low
85-215
yes/low
yes/low
yes/low
yes/med
1-211
yes/no
yes/low
yes/no
yes/low
85-211
yes/low
yes/no
yes/med
yes/med
73-211
yes/low
yes/no
yes/med
yes/low
TABLE 4
C-terminal His tag NS1 Expression/Solubility results for
NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
FL
yes/low
yes/no
no/na
yes/low
1-215
yes/no
yes/medium
yes/no
yes/no
73-215
na
na
yes/no
yes/low
85-215
yes/medium
yes/good
yes/low
yes/low
91-215
yes/low
yes/low
na
yes/low
1-211
no/na
na
yes/no
na
85-211
yes/no
yes/no
yes/low
yes/no
73-211
na
yes/no
yes/good
yes/no
91-211
yes/no
na
na
na
85-204
yes/low
yes/low
yes/low
yes/low
91-204
yes/no
yes/no
na
yes/no
Creating Attenuated Influenza Virus Strains Suitable for Avian and Human Influenza Vaccine Development. The structural information disclosed here can be combined with site-directed mutagenesis data for NS1A to engineer attenuated influenza A virus strains suitable for use as live attenuated vaccines in humans and livestock. Multiple, weakly attenuating mutations will be created in the CPSF30 and dsRNA-binding epitopes to generate NS1 proteins with reduced binding affinity in vitro. The effects of these mutations on the structural integrity of NS1A variants can be assessed with HSQC NMR data and/or crystallization and X-ray crystallography. These data will then be used to engineer viral strains of influenza A with various degrees of attenuation. These viral strains will be engineered to contain multiple base changes to minimize the potential of the virus to revert to virulence. Such influenza A viruses would be attenuated in normal cells, and in humans and animals, but would not be attenuated in cells lacking interferon genes (e.g. cell culture Vero cells), thereby enabling the production of large amounts of these attenuated viruses suitable for use as a live virus vaccine.
Methods for development of attenuated flu vaccines are described in U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,”, and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference, relevant portions incorporated herein by reference.
A person of ordinary skill in the art will understand that because of the degeneracy of the genetic code, a large number of nucleic acid sequences can be generated in accordance with this invention. The production of the viruses of the instant invention (or the respective recombinant NS1A protein or respective NS1B protein comprising said amino acid sequences) can be achieved by recombinant DNA technology. Nucleic acid sequences encoding the amino acid sequences of the instant invention can be produced using methods well known in the art, including, for example, chemical synthesis, PCR and site-directed mutagenesis.
The instant invention provides recombinant influenza A virus comprising the amino acid sequences which are at least 70% identical but less than 100% identical either to dsRNA binding domains of NS1A. These viruses may be generated, for example, by reverse genetic system, whereby influenza virus can be generated by transfection of multiple DNAs without a helper virus. This technique was described in Fodor et al., 1999. Essentially, in that study the technique involved transfecting into a host cell a combination of plasmids containing cDNAs for the viral RNA segments (including NS1 proteins), proteins of viral RNA dependent polymerase complex (PB1, PB2, and PA), and nucleoprotein. Further, it is possible to transfect host cells (such as, for example 293 cells or Vero cells) with a plasmid encoding a recombinant NS1A protein (for rescuing influenza A viral phenotype) containing the appropriate amino acid sequence of the instant invention. The resulting viruses may be used for creation of vaccines, as described below.
In another embodiment, the virus can be propagated in suitable host, such as, for example, chicken eggs, without a need for transforming a host cell with multiple plasmids. In this embodiment, essentially, clinical isolates of human influenza virus are taken from infected patients and are reassorted in embryonated chicken eggs with laboratory-adapted master strains of high-growth donor viruses.
To prepare the recombinant NS1A viruses for different purposes (including, without limitations, the use of the virus as a vaccine or a part thereof), each of these mutations may be carried out individually on constructs of NS1A suitable for biochemical characterization, possibly including but not limited to the constructs outlined in Tables 3 and 4. Other variants of NS1A or affinity tags (e.g. FLAG tags) may also be used. These proteins may be purified and characterized with respect to structural integrity by comparing the circular dichroism and/or NMR spectrum and/or X-ray crystal structures with those of the corresponding wild-type NS1 construct. The several constructs may then be assayed for dsRNA binding as described elsewhere (Chien et al., 2004), or using other methods of assessing protein-dsRNA binding affinities commonly used for such studies, such as, for example, sedimentation equilibrium, gel electrophoresis, or gel filtration chromatography. These data will be used to assess the effect of single site mutants at these sites revealed by the structural models to be important for dsRNA recognition. Further, sets of double, triple, and quadruple mutants of residues in the CPSF30 binding epitope, tetramer interface, dsRNA binding epitope, and combinations thereof would also be generated in these NS1A constructs and assessed for structural integrity and binding activities in vitro. This experimental design will allow a person of the ordinary skill in the art to identify mutant forms of NS1A and NS1A varients with minimal structural disruption but with reduced CPSF30 and/or dsRNA binding affinity.
The invention encompasses methods of selecting viruses which have the desired phenotype, i.e., viruses which have low or no dsRNA binding activity, whether obtained from natural variants, spontaneous variants (i.e., variants which evolve during virus propagation), mutagenized natural variants, reassortants and/or genetically engineered viruses. Such viruses can be best screened in differential growth assays that compare growth in host systems which have attenuated and normal immune response to influenza A viruses. Viruses which demonstrate better growth in the hosts having the attenuated response versus the normal response are selected; preferably, viruses which grow to titers at least one log greater in the host systems with the attenuated response as compared to the host system with the normal response are selected.
The present invention also encompasses methods of growing and isolating mutated viruses having altered dsRNA binding activity in cells and cell lines which naturally exhibit an attenuated response to viral infections as compared to wild-type cells. In a particular preferred embodiment, the present invention relates to methods of growing the viruses of the instant invention in Vero cells.
It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.
It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.
All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
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HEADER
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XX−XXX−XX xxxx
COMPND
−−−
REMARK
3
REMARK
3
REFINEMENT.
REMARK
3
PROGRAM:
REFMAC 5.2.0005
REMARK
3
AUTHORS:
MURSHUDOV, VAGIN, DODSON
REMARK
3
REMARK
3
REFINEMENT TARGET:
MAXIMUM LIKELIHOOD
REMARK
3
REMARK
3
DATA USED IN REFINEMENT.
REMARK
3
RESOLUTION RANGE HIGH (ANGSTROMS):
1.95
REMARK
3
RESOLUTION RANGE LOW (ANGSTROMS):
25.00
REMARK
3
DATA CUTOFF (SIGMA(F)):
NONE
REMARK
3
COMPLETENESS FOR RANGE (%):
97.88
REMARK
3
NUMBER OF REFLECTIONS:
35935
REMARK
3
REMARK
3
FIT TO DATA USED IN REFINEMENT.
REMARK
3
CROSS−VALIDATION METHOD:
THROUGHOUT
REMARK
3
FREE R VALUE TEST SET SELECTION:
RANDOM
REMARK
3
R VALUE (WORKING + TEST SET):
0.19912
REMARK
3
R VALUE (WORKING SET):
0.19794
REMARK
3
FREE R VALUE:
0.23607
REMARK
3
FREE R VALUE TEST SET SIZE (%):
3.1
REMARK
3
FREE R VALUE TEST SET COUNT:
1159
REMARK
3
REMARK
3
FIT IN THE HIGHEST RESOLUTION BIN.
REMARK
3
TOTAL NUMBER OF BINS USED:
20
REMARK
3
BIN RESOLUTION RANGE HIGH:
1.950
REMARK
3
BIN RESOLUTION RANGE LOW:
2.000
REMARK
3
REFLECTION IN BIN (WORKING SET):
2372
REMARK
3
BIN COMPLETENESS (WORKING(%):
87.48
REMARK
3
BIN R VALUE (WORKING SET):
0.251
REMARK
3
BIN FREE R VALUE SET COUNT:
66
REMARK
3
BIN FREE R VALUE:
0.310
REMARK
3
REMARK
3
NUMBER OF NON−HYDROGEN ATOMS USED IN REFINEMENT.
REMARK
3
ALL ATOMS:
3121
REMARK
3
REMARK
3
B VALUES.
REMARK
3
FROM WILSON PLOT (A**2):
NULL
REMARK
3
MEAN B VALUE (OVERALL, A**2):
36.438
REMARK
3
OVERALL ANISOTROPIC B VALUE.
REMARK
3
B11 (A**2):
1.36
REMARK
3
B22 (A**2):
1.36
REMARK
3
B33 (A**2):
−2.71
REMARK
3
B12 (A**2):
0.00
REMARK
3
B13 (A**2):
0.00
REMARK
3
B23 (A**2):
0.00
REMARK
3
REMARK
3
ESTIMATED OVERALL COORDINATE ERROR.
REMARK
3
ESU BASED ON R VALUE (A):
0.143
REMARK
3
ESU BASED ON FREE R VALUE (A):
0.138
REMARK
3
ESU BASED ON MAXIMUM LIKELIHOOD (A):
0.102
REMARK
3
ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2):
3.568
REMARK
3
REMARK
3
CORRELATION COEFFICIENTS.
REMARK
3
CORRELATION COEFFICIENT FO−FC:
0.956
REMARK
3
CORRELATION COEFFICIENT FO−FC FREE:
0.942
REMARK
3
REMARK
3
RMS DEVIATIONS FROM IDEAL VALUES
COUNT
RMS
WEIGHT
REMARK
3
BOND LENGTHS REFINED ATOMS (A):
2997
;
0.020
;
0.022
REMARK
3
BOND ANGLES REFINED ATOMS
4042
;
1.715
;
1.956
(DEGREES):
REMARK
3
TORSION ANGLES, PERIOD 1 (DEGREES):
357
;
6.180
;
5.000
REMARK
3
TORSION ANGLES, PERIOD 2 (DEGREES):
137
;
34.186
;
24.015
REMARK
3
TORSION ANGLES, PERIOD 3 (DEGREES):
548
;
14.846
;
15.000
REMARK
3
TORSION ANGLES, PERIOD 4 (DEGREES):
16
;
17.200
;
15.000
REMARK
3
CHIRAL- CENTER RESTRAINTS (A**3):
435
;
0.126
;
0.200
REMARK
3
GENERAL PLANES REFINED ATOMS (A):
2240
;
0.007
;
0.020
REMARK
3
NON-BONDED CONTACTS REFINED
1262
;
0.212
;
0.200
ATOMS (A):
REMARK
3
NON- BONDED TORSION REFINED
2012
;
0.311
;
0.200
ATOMS (A):
REMARK
3
H- BOND (X...Y) REFINED ATOMS (A):
162
;
0.165
;
0.200
REMARK
3
POTENTIAL METAL−ION REFINED
1
;
0.109
;
0.200
ATOMS (A):
REMARK
3
SYMMETRY VDW REFINED ATOMS (A):
85
;
0.232
;
0.200
REMARK
3
SYMMETRY H−BOND REFINED
14
;
0.182
;
0.200
ATOMS (A):
REMARK
3
REMARK
3
ISOTROPIC THERMAL FACTOR
COUNT
RMS
WEIGHT
RESTRAINTS.
REMARK
3
MAIN- CHAIN BOND REFINED ATOMS
1889
;
1.376
;
1.500
(A**2):
REMARK
3
MAIN- CHAIN ANGLE REFINED ATOMS
2920
;
2.197
;
2.000
(A**2):
REMARK
3
SIDE- CHAIN BOND REFINED ATOMS
1300
;
2.913
;
3.000
(A**2):
REMARK
3
SIDE- CHAIN ANGLE REFINED ATOMS
1122
;
4.495
;
4.500
(A**2):
REMARK
3
REMARK
3
NCS RESTRAINTS STATISTICS
REMARK
3
NUMBER OF NCS GROUPS:
NULL
REMARK
3
REMARK
3
REMARK
3
TLS DETAILS
REMARK
3
NUMBER OF TLS GROUPS:
NULL
REMARK
3
REMARK
3
REMARK
3
BULK SOLVENT MODELLING.
REMARK
3
METHOD USED:
MASK
REMARK
3
PARAMETERS FOR MASK CALCULATION
REMARK
3
VDW PROBE RADIUS:
1.20
REMARK
3
ION PROBE RADIUS:
0.80
REMARK
3
SHRINKAGE RADIUS:
0.80
REMARK
3
REMARK
3
OTHER REFINEMENT REMARKS:
REMARK
3
HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
REMARK
3
CRYST1
50.961
50.961
205.387
90.00
90.00
90.00
P 41
SCALE1
0.019623
0.000000
0.000000
0.00000
SCALE2
0.000000
0.019623
0.000000
0.00000
SCALE3
0.000000
0.000000
0.004869
0.00000
ATOM
1
N
PRO
A
85
−26.122
32.840
39.164
1.00
67.70
N
ATOM
2
CA
PRO
A
85
−26.884
33.641
38.196
1.00
67.41
C
ATOM
3
CB
PRO
A
85
−26.347
35.071
38.415
1.00
67.69
C
ATOM
4
CG
PRO
A
85
−25.675
35.066
39.826
1.00
68.21
C
ATOM
5
CD
PRO
A
85
−25.736
33.625
40.355
1.00
68.25
C
ATOM
6
C
PRO
A
85
−26.665
33.197
36.735
1.00
66.66
C
ATOM
7
O
PRO
A
85
−25.599
32.636
36.413
1.00
67.05
O
ATOM
8
N
ALA
A
86
−27.666
33.441
35.876
1.00
65.01
N
ATOM
9
CA
ALA
A
86
−27.562
33.211
34.427
1.00
63.22
C
ATOM
10
CB
ALA
A
86
−28.909
33.479
33.746
1.00
63.77
C
ATOM
11
C
ALA
A
86
−26.438
34.049
33.773
1.00
61.60
C
ATOM
12
O
ALA
A
86
−26.536
35.280
33.715
1.00
61.58
O
ATOM
13
N
SER
A
87
−25.385
33.361
33.294
1.00
59.11
N
ATOM
14
CA
SER
A
87
−24.164
33.987
32.734
1.00
56.32
C
ATOM
15
CB
SER
A
87
−23.014
32.968
32.609
1.00
56.60
C
ATOM
16
OG
SER
A
87
−22.933
32.092
33.722
1.00
55.71
O
ATOM
17
C
SER
A
87
−24.439
34.600
31.365
1.00
54.09
C
ATOM
18
O
SER
A
87
−25.441
34.273
30.727
1.00
53.42
O
ATOM
19
N
ARG
A
88
−23.560
35.507
30.928
1.00
51.11
N
ATOM
20
CA
ARG
A
88
−23.691
36.103
29.599
1.00
49.05
C
ATOM
21
CB
ARG
A
88
−22.704
37.255
29.435
1.00
49.01
C
ATOM
22
CG
ARG
A
88
−23.079
38.587
30.081
1.00
52.03
C
ATOM
23
CD
ARG
A
88
−21.921
39.576
29.841
1.00
51.77
C
ATOM
24
NE
ARG
A
88
−21.495
39.538
28.437
1.00
56.44
N
ATOM
25
CZ
ARG
A
88
−20.325
39.972
27.964
1.00
56.82
C
ATOM
26
NH1
ARG
A
88
−19.396
40.504
28.770
1.00
52.97
N
ATOM
27
NH2
ARG
A
88
−20.093
39.853
26.662
1.00
58.69
N
ATOM
28
C
ARG
A
88
−23.391
35.056
28.527
1.00
45.17
C
ATOM
29
O
ARG
A
88
−22.545
34.198
28.745
1.00
43.46
O
ATOM
30
N
TYR
A
89
−24.092
35.139
27.399
1.00
42.80
N
ATOM
31
CA
TYR
A
89
−23.763
34.336
26.204
1.00
42.12
C
ATOM
32
CB
TYR
A
89
−24.984
33.639
25.610
1.00
43.89
C
ATOM
33
CG
TYR
A
89
−25.584
32.586
26.481
1.00
49.25
C
ATOM
34
CD1
TYR
A
89
−26.692
32.877
27.301
1.00
53.80
C
ATOM
35
CE1
TYR
A
89
−27.278
31.876
28.129
1.00
55.07
C
ATOM
36
CZ
TYR
A
89
−26.745
30.583
28.120
1.00
53.29
C
ATOM
37
OH
TYR
A
89
−27.307
29.603
28.924
1.00
52.63
O
ATOM
38
CE2
TYR
A
89
−25.633
30.272
27.320
1.00
52.65
C
ATOM
39
CD2
TYR
A
89
−25.059
31.275
26.501
1.00
51.55
C
ATOM
40
C
TYR
A
89
−23.103
35.144
25.095
1.00
39.05
C
ATOM
41
O
TYR
A
89
−23.578
36.222
24.734
1.00
39.30
O
ATOM
42
N
ILE
A
90
−22.007
34.604
24.565
1.00
35.95
N
ATOM
43
CA
ILE
A
90
−21.374
35.101
23.343
1.00
33.00
C
ATOM
44
CB
ILE
A
90
−19.815
35.017
23.400
1.00
33.20
C
ATOM
45
CG1
ILE
A
90
−19.213
35.693
24.659
1.00
31.66
C
ATOM
46
CD1
ILE
A
90
−19.623
37.181
24.946
1.00
34.93
C
ATOM
47
CG2
ILE
A
90
−19.218
35.494
22.065
1.00
32.68
C
ATOM
48
C
ILE
A
90
−21.815
34.214
22.179
1.00
31.70
C
ATOM
49
O
ILE
A
90
−21.772
32.988
22.277
1.00
30.65
O
ATOM
50
N
THR
A
91
−22.206
34.848
21.084
1.00
30.72
N
ATOM
51
CA
THR
A
91
−22.721
34.177
19.892
1.00
30.64
C
ATOM
52
CB
THR
A
91
−24.272
34.313
19.747
1.00
30.93
C
ATOM
53
OG1
THR
A
91
−24.641
35.693
19.595
1.00
31.58
O
ATOM
54
CG2
THR
A
91
−25.010
33.726
20.961
1.00
31.12
C
ATOM
55
C
THR
A
91
−21.973
34.698
18.654
1.00
30.39
C
ATOM
56
O
THR
A
91
−22.425
35.616
18.014
1.00
29.92
O
ATOM
57
N
ASP
A
92
−20.789
34.150
18.367
1.00
29.53
N
ATOM
58
CA
ASP
A
92
−20.088
34.437
17.103
1.00
29.38
C
ATOM
59
CB
ASP
A
92
−18.705
33.737
16.987
1.00
29.06
C
ATOM
60
CG
ASP
A
92
−17.630
34.283
17.934
1.00
30.61
C
ATOM
61
OD1
ASP
A
92
−17.802
35.375
18.537
1.00
29.26
O
ATOM
62
OD2
ASP
A
92
−16.577
33.585
18.121
1.00
25.92
O
ATOM
63
C
ASP
A
92
−20.917
33.920
15.919
1.00
29.87
C
ATOM
64
O
ASP
A
92
−20.852
34.518
14.848
1.00
30.63
O
ATOM
65
N
MET
A
93
−21.646
32.798
16.090
1.00
28.80
N
ATOM
66
CA
MET
A
93
−22.334
32.178
14.985
1.00
28.53
C
ATOM
67
CB
MET
A
93
−22.254
30.625
15.045
1.00
28.56
C
ATOM
68
CG
MET
A
93
−20.873
30.056
14.617
1.00
23.17
C
ATOM
69
SD
MET
A
93
−20.816
28.244
14.793
1.00
22.81
S
ATOM
70
CE
MET
A
93
−20.351
28.121
16.505
1.00
21.77
C
ATOM
71
C
MET
A
93
−23.785
32.591
14.932
1.00
31.52
C
ATOM
72
O
MET
A
93
−24.416
32.810
15.973
1.00
32.72
O
ATOM
73
N
THR
A
94
−24.311
32.686
13.709
1.00
33.84
N
ATOM
74
CA
THR
A
94
−25.754
32.818
13.520
1.00
35.14
C
ATOM
75
CB
THR
A
94
−26.080
33.245
12.094
1.00
35.65
C
ATOM
76
OG1
THR
A
94
−25.554
32.285
11.173
1.00
35.99
O
ATOM
77
CG2
THR
A
94
−25.481
34.615
11.807
1.00
36.80
C
ATOM
78
C
THR
A
94
−26.448
31.512
13.841
1.00
35.97
C
ATOM
79
O
THR
A
94
−25.818
30.446
13.913
1.00
34.20
O
ATOM
80
N
ILE
A
95
−27.761
31.587
14.029
1.00
36.97
N
ATOM
81
CA
ILE
A
95
−28.575
30.410
14.266
1.00
38.79
C
ATOM
82
CB
ILE
A
95
−30.070
30.801
14.496
1.00
38.82
C
ATOM
83
CG1
ILE
A
95
−30.205
31.659
15.779
1.00
41.36
C
ATOM
84
CD1
ILE
A
95
−31.709
31.841
16.326
1.00
42.00
C
ATOM
85
CG2
ILE
A
95
−30.911
29.558
14.598
1.00
41.63
C
ATOM
86
C
ILE
A
95
−28.396
29.378
13.116
1.00
37.69
C
ATOM
87
O
ILE
A
95
−28.268
28.199
13.365
1.00
38.70
O
ATOM
88
N
GLU
A
96
−28.378
29.842
11.878
1.00
36.92
N
ATOM
89
CA
GLU
A
96
−28.104
28.999
10.700
1.00
36.29
C
ATOM
90
CB
GLU
A
96
−28.239
29.823
9.409
1.00
36.39
C
ATOM
91
CG
GLU
A
96
−28.227
29.016
8.087
1.00
38.37
C
ATOM
92
CD
GLU
A
96
−26.817
28.589
7.614
1.00
40.56
C
ATOM
93
OE1
GLU
A
96
−25.874
29.406
7.689
1.00
39.66
O
ATOM
94
OE2
GLU
A
96
−26.666
27.421
7.174
1.00
40.00
O
ATOM
95
C
GLU
A
96
−26.709
28.344
10.788
1.00
35.41
C
ATOM
96
O
GLU
A
96
−26.605
27.137
10.614
1.00
33.83
O
ATOM
97
N
GLU
A
97
−25.657
29.114
11.117
1.00
34.89
N
ATOM
98
CA
GLU
A
97
−24.290
28.538
11.192
1.00
34.19
C
ATOM
99
CB
GLU
A
97
−23.215
29.612
11.389
1.00
34.50
C
ATOM
100
CG
GLU
A
97
−22.913
30.437
10.153
1.00
34.90
C
ATOM
101
CD
GLU
A
97
−22.021
31.629
10.505
1.00
38.47
C
ATOM
102
OE1
GLU
A
97
−22.183
32.188
11.630
1.00
34.46
O
ATOM
103
OE2
GLU
A
97
−21.153
31.993
9.675
1.00
39.78
O
ATOM
104
C
GLU
A
97
−24.222
27.492
12.285
1.00
34.41
C
ATOM
105
O
GLU
A
97
−23.610
26.431
12.128
1.00
33.26
O
ATOM
106
N
LEU
A
98
−24.931
27.757
13.379
1.00
33.38
N
ATOM
107
CA
LEU
A
98
−24.975
26.854
14.496
1.00
33.56
C
ATOM
108
CB
LEU
A
98
−25.625
27.616
15.676
1.00
35.16
C
ATOM
109
CG
LEU
A
98
−25.697
27.103
17.089
1.00
36.28
C
ATOM
110
CD1
LEU
A
98
−24.280
27.030
17.629
1.00
37.99
C
ATOM
111
CD2
LEU
A
98
−26.556
28.164
17.855
1.00
36.53
C
ATOM
112
C
LEU
A
98
−25.721
25.558
14.186
1.00
33.48
C
ATOM
113
O
LEU
A
98
−25.383
24.495
14.740
1.00
31.52
O
ATOM
114
N
SER
A
99
−26.735
25.649
13.311
1.00
32.52
N
ATOM
115
CA
SER
A
99
−27.648
24.548
13.055
1.00
34.15
C
ATOM
116
CB
SER
A
99
−29.071
25.062
12.750
1.00
33.43
C
ATOM
117
OG
SER
A
99
−29.498
25.903
13.802
1.00
40.37
O
ATOM
118
C
SER
A
99
−27.246
23.698
11.864
1.00
32.87
C
ATOM
119
O
SER
A
99
−27.754
22.584
11.728
1.00
32.22
O
ATOM
120
N
ARG
A
100
−26.348
24.228
11.031
1.00
31.55
N
ATOM
121
CA
ARG
A
100
−25.947
23.591
9.759
1.00
31.41
C
ATOM
122
CB
ARG
A
100
−24.975
24.509
9.028
1.00
30.90
C
ATOM
123
CG
ARG
A
100
−24.884
24.295
7.526
1.00
30.96
C
ATOM
124
CD
ARG
A
100
−23.727
25.099
6.940
1.00
30.21
C
ATOM
125
NE
ARG
A
100
−23.929
26.551
7.061
1.00
31.23
N
ATOM
126
CZ
ARG
A
100
−22.966
27.437
6.886
1.00
33.84
C
ATOM
127
NH1
ARG
A
100
−21.733
27.018
6.593
1.00
32.14
N
ATOM
128
NH2
ARG
A
100
−23.220
28.737
7.013
1.00
33.44
N
ATOM
129
C
ARG
A
100
−25.234
22.286
10.023
1.00
30.72
C
ATOM
130
O
ARG
A
100
−24.495
22.186
10.990
1.00
31.73
O
ATOM
131
N
ASP
A
101
−25.459
21.277
9.193
1.00
30.35
N
ATOM
132
CA
ASP
A
101
−24.662
20.072
9.267
1.00
30.10
C
ATOM
133
CB
ASP
A
101
−25.502
18.809
9.060
1.00
30.91
C
ATOM
134
CG
ASP
A
101
−26.681
18.707
10.025
1.00
31.96
C
ATOM
135
OD1
ASP
A
101
−26.458
18.846
11.256
1.00
33.73
O
ATOM
136
OD2
ASP
A
101
−27.815
18.479
9.538
1.00
31.46
O
ATOM
137
C
ASP
A
101
−23.617
20.188
8.171
1.00
29.73
C
ATOM
138
O
ASP
A
101
−23.823
20.894
7.189
1.00
30.58
O
ATOM
139
N
TRP
A
102
−22.472
19.540
8.345
1.00
29.30
N
ATOM
140
CA
TRP
A
102
−21.402
19.662
7.352
1.00
26.90
C
ATOM
141
CB
TRP
A
102
−20.371
20.709
7.759
1.00
27.28
C
ATOM
142
CG
TRP
A
102
−19.709
20.410
9.076
1.00
26.50
C
ATOM
143
CD1
TRP
A
102
−20.266
20.538
10.322
1.00
28.05
C
ATOM
144
NE1
TRP
A
102
−19.366
20.185
11.298
1.00
25.18
N
ATOM
145
CE2
TRP
A
102
−18.179
19.851
10.700
1.00
27.63
C
ATOM
146
CD2
TRP
A
102
−18.363
19.979
9.285
1.00
27.61
C
ATOM
147
CE3
TRP
A
102
−17.290
19.692
8.432
1.00
24.42
C
ATOM
148
CZ3
TRP
A
102
−16.064
19.254
9.001
1.00
24.78
C
ATOM
149
CH2
TRP
A
102
−15.922
19.115
10.407
1.00
27.13
C
ATOM
150
CZ2
TRP
A
102
−16.979
19.406
11.266
1.00
27.85
C
ATOM
151
C
TRP
A
102
−20.799
18.285
7.086
1.00
27.67
C
ATOM
152
O
TRP
A
102
−21.014
17.347
7.844
1.00
26.73
O
ATOM
153
N
PHE
A
103
−20.040
18.169
5.999
1.00
27.38
N
ATOM
154
CA
PHE
A
103
−19.555
16.865
5.544
1.00
26.65
C
ATOM
155
CB
PHE
A
103
−20.066
16.694
4.095
1.00
27.13
C
ATOM
156
CG
PHE
A
103
−19.353
15.647
3.275
1.00
29.74
C
ATOM
157
CD1
PHE
A
103
−19.838
14.339
3.223
1.00
32.10
C
ATOM
158
CE1
PHE
A
103
−19.198
13.365
2.419
1.00
29.36
C
ATOM
159
CZ
PHE
A
103
−18.095
13.730
1.649
1.00
31.44
C
ATOM
160
CE2
PHE
A
103
−17.614
15.036
1.668
1.00
34.30
C
ATOM
161
CD2
PHE
A
103
−18.245
15.993
2.478
1.00
33.21
C
ATOM
162
C
PHE
A
103
−18.031
16.886
5.539
1.00
25.08
C
ATOM
163
O
PHE
A
103
−17.427
17.901
5.181
1.00
25.47
O
ATOM
164
N
MET
A
104
−17.418
15.781
5.953
1.00
24.11
N
ATOM
165
CA
MET
A
104
−15.946
15.601
5.888
1.00
24.78
C
ATOM
166
CB
MET
A
104
−15.339
15.135
7.242
1.00
23.15
C
ATOM
167
CG
MET
A
104
−15.578
16.116
8.425
1.00
25.55
C
ATOM
168
SD
MET
A
104
−15.331
15.278
10.011
1.00
27.07
S
ATOM
169
CE
MET
A
104
−16.966
14.670
10.253
1.00
27.39
C
ATOM
170
C
MET
A
104
−15.672
14.532
4.832
1.00
24.85
C
ATOM
171
O
MET
A
104
−16.247
13.450
4.874
1.00
25.29
O
ATOM
172
N
LEU
A
105
−14.780
14.842
3.893
1.00
25.30
N
ATOM
173
CA
LEU
A
105
−14.315
13.870
2.911
1.00
24.88
C
ATOM
174
CB
LEU
A
105
−13.577
14.626
1.795
1.00
24.53
C
ATOM
175
CG
LEU
A
105
−13.109
13.799
0.593
1.00
30.23
C
ATOM
176
CD1
LEU
A
105
−14.315
13.128
−0.104
1.00
27.68
C
ATOM
177
CD2
LEU
A
105
−12.328
14.697
−0.333
1.00
31.62
C
ATOM
178
C
LEU
A
105
−13.473
12.817
3.534
1.00
24.44
C
ATOM
179
O
LEU
A
105
−13.600
11.624
3.187
1.00
25.09
O
ATOM
180
N
MET
A
106
−12.600
13.229
4.472
1.00
23.86
N
ATOM
181
CA
MET
A
106
−11.733
12.325
5.187
1.00
23.48
C
ATOM
182
CB
MET
A
106
−10.253
12.672
4.853
1.00
23.02
C
ATOM
183
CG
MET
A
106
−9.897
12.294
3.344
1.00
25.01
C
ATOM
184
SD
MET
A
106
−8.226
12.780
2.955
1.00
24.98
S
ATOM
185
CE
MET
A
106
−8.504
13.050
1.171
1.00
33.15
C
ATOM
186
C
MET
A
106
−11.987
12.547
6.702
1.00
24.02
C
ATOM
187
O
MET
A
106
−11.212
13.271
7.351
1.00
22.17
O
ATOM
188
N
PRO
A
107
−13.070
11.957
7.235
1.00
25.50
N
ATOM
189
CA
PRO
A
107
−13.453
12.363
8.597
1.00
25.66
C
ATOM
190
CB
PRO
A
107
−14.813
11.708
8.812
1.00
26.36
C
ATOM
191
CG
PRO
A
107
−15.014
10.716
7.645
1.00
27.67
C
ATOM
192
CD
PRO
A
107
−13.963
10.924
6.649
1.00
26.26
C
ATOM
193
C
PRO
A
107
−12.456
11.954
9.666
1.00
26.62
C
ATOM
194
O
PRO
A
107
−11.874
10.860
9.627
1.00
25.19
O
ATOM
195
N
LYS
A
108
−12.231
12.859
10.610
1.00
27.63
N
ATOM
196
CA
LYS
A
108
−11.452
12.532
11.791
1.00
26.56
C
ATOM
197
CB
LYS
A
108
−10.124
13.291
11.818
1.00
27.79
C
ATOM
198
CG
LYS
A
108
−9.108
13.047
10.659
1.00
28.05
C
ATOM
199
CD
LYS
A
108
−8.192
11.916
10.934
1.00
31.20
C
ATOM
200
CE
LYS
A
108
−8.719
10.611
10.548
1.00
30.45
C
ATOM
201
NZ
LYS
A
108
−8.945
10.441
9.045
1.00
33.91
N
ATOM
202
C
LYS
A
108
−12.304
13.026
12.953
1.00
27.72
C
ATOM
203
O
LYS
A
108
−12.825
14.177
12.935
1.00
24.97
O
ATOM
204
N
GLN
A
109
−12.403
12.194
13.977
1.00
27.58
N
ATOM
205
CA
GLN
A
109
−13.182
12.573
15.157
1.00
30.64
C
ATOM
206
CB
GLN
A
109
−14.621
12.111
15.006
1.00
29.87
C
ATOM
207
CG
GLN
A
109
−15.459
12.288
16.241
1.00
39.27
C
ATOM
208
CD
GLN
A
109
−16.683
11.376
16.235
1.00
46.13
C
ATOM
209
OE1
GLN
A
109
−16.724
10.376
16.970
1.00
48.01
O
ATOM
210
NE2
GLN
A
109
−17.666
11.693
15.375
1.00
46.81
N
ATOM
211
C
GLN
A
109
−12.504
11.988
16.372
1.00
30.84
C
ATOM
212
O
GLN
A
109
−12.006
10.853
16.332
1.00
31.32
O
ATOM
213
N
LYS
A
110
−12.372
12.810
17.404
1.00
30.66
N
ATOM
214
CA
LYS
A
110
−11.746
12.430
18.662
1.00
33.30
C
ATOM
215
CB
LYS
A
110
−10.384
13.105
18.838
1.00
32.59
C
ATOM
216
CG
LYS
A
110
−9.599
12.479
19.944
1.00
39.86
C
ATOM
217
CD
LYS
A
110
−8.308
13.201
20.198
1.00
44.72
C
ATOM
218
CE
LYS
A
110
−7.424
12.330
21.064
1.00
49.17
C
ATOM
219
NZ
LYS
A
110
−5.981
12.798
21.028
1.00
51.75
N
ATOM
220
C
LYS
A
110
−12.641
12.944
19.806
1.00
33.85
C
ATOM
221
O
LYS
A
110
−13.014
14.135
19.846
1.00
32.23
O
ATOM
222
N
VAL
A
111
−12.953
12.046
20.738
1.00
34.29
N
ATOM
223
CA
VAL
A
111
−13.601
12.447
21.969
1.00
35.38
C
ATOM
224
CB
VAL
A
111
−14.656
11.399
22.405
1.00
35.08
C
ATOM
225
CG1
VAL
A
111
−15.253
11.774
23.720
1.00
36.51
C
ATOM
226
CG2
VAL
A
111
−15.780
11.326
21.306
1.00
34.54
C
ATOM
227
C
VAL
A
111
−12.464
12.658
22.927
1.00
36.40
C
ATOM
228
O
VAL
A
111
−11.677
11.747
23.143
1.00
37.57
O
ATOM
229
N
GLU
A
112
−12.287
13.899
23.387
1.00
36.90
N
ATOM
230
CA
GLU
A
112
−11.288
14.204
24.400
1.00
38.96
C
ATOM
231
CB
GLU
A
112
−10.265
15.217
23.913
1.00
39.19
C
ATOM
232
CG
GLU
A
112
−9.175
14.530
23.156
1.00
46.21
C
ATOM
233
CD
GLU
A
112
−7.912
15.349
22.990
1.00
51.55
C
ATOM
234
OE1
GLU
A
112
−7.283
15.197
21.928
1.00
53.26
O
ATOM
235
OE2
GLU
A
112
−7.547
16.134
23.906
1.00
56.88
O
ATOM
236
C
GLU
A
112
−12.007
14.718
25.634
1.00
38.39
C
ATOM
237
O
GLU
A
112
−12.469
15.865
25.685
1.00
36.96
O
ATOM
238
N
GLY
A
113
−12.140
13.822
26.601
1.00
39.27
N
ATOM
239
CA
GLY
A
113
−12.917
14.119
27.796
1.00
38.12
C
ATOM
240
C
GLY
A
113
−14.353
14.437
27.464
1.00
36.64
C
ATOM
241
O
GLY
A
113
−15.033
13.655
26.776
1.00
38.16
O
ATOM
242
N
PRO
A
114
−14.849
15.576
27.964
1.00
33.88
N
ATOM
243
CA
PRO
A
114
−16.237
15.943
27.762
1.00
32.13
C
ATOM
244
CB
PRO
A
114
−16.492
16.931
28.916
1.00
32.60
C
ATOM
245
CG
PRO
A
114
−15.165
17.627
29.055
1.00
31.81
C
ATOM
246
CD
PRO
A
114
−14.126
16.576
28.781
1.00
34.84
C
ATOM
247
C
PRO
A
114
−16.509
16.645
26.405
1.00
29.72
C
ATOM
248
O
PRO
A
114
−17.657
17.067
26.146
1.00
28.42
O
ATOM
249
N
LEU
A
115
−15.499
16.717
25.536
1.00
28.35
N
ATOM
250
CA
LEU
A
115
−15.700
17.376
24.223
1.00
27.24
C
ATOM
251
CB
LEU
A
115
−14.794
18.599
24.129
1.00
27.96
C
ATOM
252
CG
LEU
A
115
−14.946
19.667
25.243
1.00
26.94
C
ATOM
253
CD1
LEU
A
115
−13.750
20.612
25.196
1.00
27.95
C
ATOM
254
CD2
LEU
A
115
−16.251
20.417
25.099
1.00
29.72
C
ATOM
255
C
LEU
A
115
−15.357
16.470
23.033
1.00
27.21
C
ATOM
256
O
LEU
A
115
−14.434
15.672
23.116
1.00
27.09
O
ATOM
257
N
CYS
A
116
−16.031
16.713
21.914
1.00
27.45
N
ATOM
258
CA
CYS
A
116
−15.783
15.992
20.659
1.00
26.39
C
ATOM
259
CB
CYS
A
116
−17.108
15.497
20.090
1.00
26.69
C
ATOM
260
SG
CYS
A
116
−16.868
14.551
18.501
1.00
31.80
S
ATOM
261
C
CYS
A
116
−15.120
16.929
19.656
1.00
25.74
C
ATOM
262
O
CYS
A
116
−15.639
18.029
19.409
1.00
25.83
O
ATOM
263
N
ILE
A
117
−13.960
16.523
19.126
1.00
24.09
N
ATOM
264
CA
ILE
A
117
−13.283
17.265
18.048
1.00
24.27
C
ATOM
265
CB
ILE
A
117
−11.755
17.349
18.356
1.00
25.27
C
ATOM
266
CG1
ILE
A
117
−11.517
17.862
19.806
1.00
23.31
C
ATOM
267
CD1
ILE
A
117
−10.154
17.452
20.379
1.00
26.08
C
ATOM
268
CG2
ILE
A
117
−11.015
18.197
17.315
1.00
22.67
C
ATOM
269
C
ILE
A
117
−13.472
16.573
16.692
1.00
23.94
C
ATOM
270
O
ILE
A
117
−13.241
15.340
16.562
1.00
23.40
O
ATOM
271
N
ARG
A
118
−13.839
17.358
15.693
1.00
22.86
N
ATOM
272
CA
ARG
A
118
−13.972
16.851
14.336
1.00
23.41
C
ATOM
273
CB
ARG
A
118
−15.425
16.931
13.889
1.00
24.33
C
ATOM
274
CG
ARG
A
118
−16.195
15.760
14.310
1.00
26.67
C
ATOM
275
CD
ARG
A
118
−17.648
16.145
14.171
1.00
36.06
C
ATOM
276
NE
ARG
A
118
−18.440
15.040
14.612
1.00
41.48
N
ATOM
277
CZ
ARG
A
118
−19.612
15.131
15.215
1.00
45.56
C
ATOM
278
NH1
ARG
A
118
−20.146
16.313
15.465
1.00
46.68
N
ATOM
279
NH2
ARG
A
118
−20.228
14.012
15.596
1.00
45.78
N
ATOM
280
C
ARG
A
118
−13.198
17.713
13.379
1.00
23.69
C
ATOM
281
O
ARG
A
118
−13.212
18.954
13.476
1.00
22.65
O
ATOM
282
N
ILE
A
119
−12.562
17.060
12.409
1.00
23.73
N
ATOM
283
CA
ILE
A
119
−11.831
17.816
11.420
1.00
24.09
C
ATOM
284
CB
ILE
A
119
−10.412
18.129
11.928
1.00
24.22
C
ATOM
285
CG1
ILE
A
119
−9.636
18.940
10.882
1.00
26.11
C
ATOM
286
CD1
ILE
A
119
−8.270
19.415
11.340
1.00
27.40
C
ATOM
287
CG2
ILE
A
119
−9.677
16.828
12.269
1.00
26.48
C
ATOM
288
C
ILE
A
119
−11.827
17.045
10.087
1.00
23.09
C
ATOM
289
O
ILE
A
119
−11.823
15.831
10.101
1.00
24.06
O
ATOM
290
N
ASP
A
120
−11.950
17.754
8.967
1.00
21.94
N
ATOM
291
CA
ASP
A
120
−11.754
17.122
7.654
1.00
21.86
C
ATOM
292
CB
ASP
A
120
−12.475
17.904
6.535
1.00
22.15
C
ATOM
293
CG
ASP
A
120
−12.612
17.057
5.250
1.00
23.64
C
ATOM
294
OD1
ASP
A
120
−11.983
15.954
5.179
1.00
24.29
O
ATOM
295
OD2
ASP
A
120
−13.343
17.458
4.348
1.00
23.75
O
ATOM
296
C
ASP
A
120
−10.269
17.079
7.331
1.00
21.18
C
ATOM
297
O
ASP
A
120
−9.679
18.112
7.116
1.00
21.54
O
ATOM
298
N
GLN
A
121
−9.681
15.887
7.316
1.00
21.00
N
ATOM
299
CA
GLN
A
121
−8.259
15.688
6.914
1.00
21.84
C
ATOM
300
CB
GLN
A
121
−7.873
14.225
7.121
1.00
22.28
C
ATOM
301
CG
GLN
A
121
−6.428
13.911
6.740
1.00
24.84
C
ATOM
302
CD
GLN
A
121
−5.968
12.511
7.069
1.00
25.52
C
ATOM
303
OE1
GLN
A
121
−6.754
11.585
7.276
1.00
23.53
O
ATOM
304
NE2
GLN
A
121
−4.627
12.340
7.096
1.00
25.16
N
ATOM
305
C
GLN
A
121
−7.981
16.150
5.467
1.00
22.62
C
ATOM
306
O
GLN
A
121
−6.829
16.437
5.080
1.00
21.93
O
ATOM
307
N
ALA
A
122
−9.054
16.261
4.685
1.00
21.71
N
ATOM
308
CA
ALA
A
122
−8.912
16.617
3.256
1.00
21.69
C
ATOM
309
CB
ALA
A
122
−10.181
16.141
2.494
1.00
19.71
C
ATOM
310
C
ALA
A
122
−8.662
18.107
3.052
1.00
22.50
C
ATOM
311
O
ALA
A
122
−8.187
18.546
1.985
1.00
23.74
O
ATOM
312
N
ILE
A
123
−8.969
18.924
4.058
1.00
22.64
N
ATOM
313
CA
ILE
A
123
−8.908
20.394
3.883
1.00
22.96
C
ATOM
314
CB
ILE
A
123
−9.911
21.109
4.803
1.00
23.42
C
ATOM
315
CG1
ILE
A
123
−11.364
20.728
4.413
1.00
24.78
C
ATOM
316
CD1
ILE
A
123
−11.800
21.234
3.011
1.00
28.40
C
ATOM
317
CG2
ILE
A
123
−9.756
22.634
4.681
1.00
22.20
C
ATOM
318
C
ILE
A
123
−7.508
20.981
4.108
1.00
25.70
C
ATOM
319
O
ILE
A
123
−6.947
20.792
5.178
1.00
25.29
O
ATOM
320
N
MET
A
124
−6.943
21.662
3.092
1.00
25.17
N
ATOM
321
CA
MET
A
124
−5.579
22.183
3.163
1.00
28.51
C
ATOM
322
CB
MET
A
124
−4.655
21.297
2.337
1.00
27.78
C
ATOM
323
CG
MET
A
124
−4.771
19.813
2.656
1.00
30.26
C
ATOM
324
SD
MET
A
124
−3.484
18.782
1.811
1.00
33.51
S
ATOM
325
CE
MET
A
124
−2.059
19.361
2.723
1.00
37.42
C
ATOM
326
C
MET
A
124
−5.578
23.562
2.553
1.00
28.55
C
ATOM
327
O
MET
A
124
−6.493
23.905
1.787
1.00
27.92
O
ATOM
328
N
ASP
A
125
−4.559
24.344
2.895
1.00
29.74
N
ATOM
329
CA
ASP
A
125
−4.215
25.614
2.253
1.00
32.07
C
ATOM
330
CB
ASP
A
125
−3.799
25.405
0.762
1.00
33.16
C
ATOM
331
CG
ASP
A
125
−2.736
24.338
0.604
1.00
35.13
C
ATOM
332
OD1
ASP
A
125
−1.696
24.451
1.278
1.00
36.19
O
ATOM
333
OD2
ASP
A
125
−2.941
23.385
−0.186
1.00
41.35
O
ATOM
334
C
ASP
A
125
−5.240
26.719
2.323
1.00
32.12
C
ATOM
335
O
ASP
A
125
−5.180
27.626
1.509
1.00
33.38
O
ATOM
336
N
LYS
A
126
−6.148
26.691
3.299
1.00
31.07
N
ATOM
337
CA
LYS
A
126
−7.178
27.720
3.386
1.00
30.62
C
ATOM
338
CB
LYS
A
126
−8.564
27.049
3.449
1.00
32.29
C
ATOM
339
CG
LYS
A
126
−8.996
26.577
2.028
1.00
35.51
C
ATOM
340
CD
LYS
A
126
−10.152
25.660
2.060
1.00
43.65
C
ATOM
341
CE
LYS
A
126
−10.660
25.433
0.631
1.00
44.47
C
ATOM
342
NZ
LYS
A
126
−11.170
26.689
−0.085
1.00
46.44
N
ATOM
343
C
LYS
A
126
−6.952
28.713
4.534
1.00
29.60
C
ATOM
344
O
LYS
A
126
−6.222
28.422
5.467
1.00
30.24
O
ATOM
345
N
ASN
A
127
−7.527
29.897
4.438
1.00
29.11
N
ATOM
346
CA
ASN
A
127
−7.523
30.805
5.578
1.00
29.06
C
ATOM
347
CB
ASN
A
127
−7.591
32.243
5.112
1.00
29.91
C
ATOM
348
CG
ASN
A
127
−6.308
32.677
4.437
1.00
33.89
C
ATOM
349
OD1
ASN
A
127
−5.214
32.543
4.998
1.00
36.73
O
ATOM
350
ND2
ASN
A
127
−6.427
33.183
3.229
1.00
37.36
N
ATOM
351
C
ASN
A
127
−8.789
30.387
6.358
1.00
28.50
C
ATOM
352
O
ASN
A
127
−9.860
30.326
5.787
1.00
26.56
O
ATOM
353
N
ILE
A
128
−8.625
30.078
7.639
1.00
27.29
N
ATOM
354
CA
ILE
A
128
−9.706
29.462
8.437
1.00
27.38
C
ATOM
355
CB
ILE
A
128
−9.295
28.032
8.952
1.00
27.42
C
ATOM
356
CG1
ILE
A
128
−9.024
27.037
7.799
1.00
27.03
C
ATOM
357
CD1
ILE
A
128
−10.184
26.824
6.863
1.00
28.44
C
ATOM
358
CG2
ILE
A
128
−10.342
27.441
9.962
1.00
26.81
C
ATOM
359
C
ILE
A
128
−9.957
30.371
9.641
1.00
27.01
C
ATOM
360
O
ILE
A
128
−9.014
30.865
10.239
1.00
27.70
O
ATOM
361
N
MET
A
129
−11.206
30.566
10.031
1.00
27.13
N
ATOM
362
CA
MET
A
129
−11.476
31.400
11.217
1.00
27.30
C
ATOM
363
CB
MET
A
129
−12.306
32.631
10.834
1.00
27.31
C
ATOM
364
CG
MET
A
129
−12.890
33.479
12.058
1.00
28.79
C
ATOM
365
SD
MET
A
129
−11.620
34.344
12.939
1.00
32.60
S
ATOM
366
CE
MET
A
129
−11.410
35.688
11.799
1.00
39.01
C
ATOM
367
C
MET
A
129
−12.264
30.526
12.183
1.00
26.82
C
ATOM
368
O
MET
A
129
−13.285
29.938
11.788
1.00
27.01
O
ATOM
369
N
LEU
A
130
−11.813
30.470
13.432
1.00
26.13
N
ATOM
370
CA
LEU
A
130
−12.575
29.765
14.497
1.00
26.12
C
ATOM
371
CB
LEU
A
130
−11.618
29.297
15.610
1.00
24.84
C
ATOM
372
CG
LEU
A
130
−10.485
28.337
15.243
1.00
27.14
C
ATOM
373
CD1
LEU
A
130
−10.087
27.626
16.479
1.00
22.57
C
ATOM
374
CD2
LEU
A
130
−10.891
27.282
14.117
1.00
22.23
C
ATOM
375
C
LEU
A
130
−13.601
30.733
15.080
1.00
25.81
C
ATOM
376
O
LEU
A
130
−13.231
31.837
15.498
1.00
26.04
O
ATOM
377
N
LYS
A
131
−14.873
30.330
15.076
1.00
26.76
N
ATOM
378
CA
LYS
A
131
−15.956
31.068
15.722
1.00
26.56
C
ATOM
379
CB
LYS
A
131
−17.004
31.490
14.684
1.00
27.61
C
ATOM
380
CG
LYS
A
131
−16.533
32.568
13.680
1.00
28.89
C
ATOM
381
CD
LYS
A
131
−17.691
32.884
12.680
1.00
28.82
C
ATOM
382
CE
LYS
A
131
−17.415
34.227
12.031
1.00
38.35
C
ATOM
383
NZ
LYS
A
131
−18.327
34.532
10.898
1.00
41.90
N
ATOM
384
C
LYS
A
131
−16.645
30.157
16.768
1.00
26.72
C
ATOM
385
O
LYS
A
131
−16.730
28.927
16.598
1.00
24.29
O
ATOM
386
N
ALA
A
132
−17.188
30.754
17.832
1.00
24.37
N
ATOM
387
CA
ALA
A
132
−17.802
29.955
18.881
1.00
23.81
C
ATOM
388
CB
ALA
A
132
−16.725
29.487
19.941
1.00
23.01
C
ATOM
389
C
ALA
A
132
−18.968
30.664
19.540
1.00
24.34
C
ATOM
390
O
ALA
A
132
−19.104
31.907
19.494
1.00
24.27
O
ATOM
391
N
ASN
A
133
−19.845
29.844
20.107
1.00
24.68
N
ATOM
392
CA
ASN
A
133
−20.919
30.315
20.981
1.00
24.43
C
ATOM
393
CB
ASN
A
133
−22.314
29.912
20.475
1.00
23.91
C
ATOM
394
CG
ASN
A
133
−22.739
30.645
19.185
1.00
27.90
C
ATOM
395
OD1
ASN
A
133
−21.937
31.202
18.437
1.00
29.10
O
ATOM
396
ND2
ASN
A
133
−24.037
30.641
18.941
1.00
29.92
N
ATOM
397
C
ASN
A
133
−20.631
29.666
22.321
1.00
23.54
C
ATOM
398
O
ASN
A
133
−20.369
28.458
22.420
1.00
21.57
O
ATOM
399
N
PHE
A
134
−20.630
30.478
23.364
1.00
23.58
N
ATOM
400
CA
PHE
A
134
−20.216
30.016
24.672
1.00
23.28
C
ATOM
401
CB
PHE
A
134
−18.686
29.889
24.725
1.00
23.19
C
ATOM
402
CG
PHE
A
134
−17.902
31.138
24.314
1.00
24.74
C
ATOM
403
CD1
PHE
A
134
−17.415
32.026
25.291
1.00
24.85
C
ATOM
404
CE1
PHE
A
134
−16.650
33.169
24.927
1.00
26.78
C
ATOM
405
CZ
PHE
A
134
−16.343
33.397
23.561
1.00
24.67
C
ATOM
406
CE2
PHE
A
134
−16.823
32.475
22.585
1.00
25.59
C
ATOM
407
CD2
PHE
A
134
−17.603
31.398
22.973
1.00
22.93
C
ATOM
408
C
PHE
A
134
−20.692
30.994
25.723
1.00
25.08
C
ATOM
409
O
PHE
A
134
−20.852
32.198
25.446
1.00
24.04
O
ATOM
410
N
SER
A
135
−20.907
30.505
26.947
1.00
27.07
N
ATOM
411
CA
SER
A
135
−21.114
31.469
28.052
1.00
27.47
C
ATOM
412
CB
SER
A
135
−22.052
30.866
29.115
1.00
28.10
C
ATOM
413
OG
SER
A
135
−21.485
29.691
29.625
1.00
27.20
O
ATOM
414
C
SER
A
135
−19.779
31.893
28.672
1.00
28.03
C
ATOM
415
O
SER
A
135
−18.787
31.176
28.560
1.00
27.68
O
ATOM
416
N
VAL
A
136
−19.759
33.076
29.322
1.00
27.28
N
ATOM
417
CA
VAL
A
136
−18.598
33.610
29.998
1.00
27.41
C
ATOM
418
CB
VAL
A
136
−18.080
34.893
29.301
1.00
27.85
C
ATOM
419
CG1
VAL
A
136
−17.743
34.601
27.826
1.00
26.37
C
ATOM
420
CG2
VAL
A
136
−19.146
35.948
29.291
1.00
28.25
C
ATOM
421
C
VAL
A
136
−18.984
33.932
31.476
1.00
27.55
C
ATOM
422
O
VAL
A
136
−20.127
34.219
31.766
1.00
28.10
O
ATOM
423
N
ILE
A
137
−18.023
33.867
32.365
1.00
28.59
N
ATOM
424
CA
ILE
A
137
−18.216
34.244
33.773
1.00
30.78
C
ATOM
425
CB
ILE
A
137
−18.669
32.988
34.633
1.00
31.59
C
ATOM
426
CG1
ILE
A
137
−19.278
33.429
35.970
1.00
33.63
C
ATOM
427
CD1
ILE
A
137
−19.700
32.180
36.817
1.00
33.97
C
ATOM
428
CG2
ILE
A
137
−17.505
31.987
34.863
1.00
30.94
C
ATOM
429
C
ILE
A
137
−16.849
34.653
34.155
1.00
29.64
C
ATOM
430
O
ILE
A
137
−15.907
34.068
33.633
1.00
29.94
O
ATOM
431
N
PHE
A
138
−16.694
35.682
35.016
1.00
29.62
N
ATOM
432
CA
PHE
A
138
−15.376
36.106
35.473
1.00
27.79
C
ATOM
433
CB
PHE
A
138
−14.703
35.101
36.440
1.00
28.87
C
ATOM
434
CG
PHE
A
138
−15.633
34.568
37.491
1.00
31.41
C
ATOM
435
CD1
PHE
A
138
−15.510
33.255
37.960
1.00
33.05
C
ATOM
436
CE1
PHE
A
138
−16.400
32.772
38.924
1.00
32.87
C
ATOM
437
CZ
PHE
A
138
−17.415
33.603
39.441
1.00
32.93
C
ATOM
438
CE2
PHE
A
138
−17.535
34.898
38.987
1.00
32.39
C
ATOM
439
CD2
PHE
A
138
−16.637
35.374
38.008
1.00
31.10
C
ATOM
440
C
PHE
A
138
−14.432
36.427
34.313
1.00
27.04
C
ATOM
441
O
PHE
A
138
−13.237
36.182
34.391
1.00
26.40
O
ATOM
442
N
ASP
A
139
−14.950
37.048
33.271
1.00
27.25
N
ATOM
443
CA
ASP
A
139
−14.059
37.476
32.165
1.00
28.11
C
ATOM
444
CB
ASP
A
139
−12.995
38.467
32.686
1.00
26.07
C
ATOM
445
CG
ASP
A
139
−12.315
39.241
31.545
1.00
24.48
C
ATOM
446
OD1
ASP
A
139
−13.054
39.624
30.621
1.00
23.66
O
ATOM
447
OD2
ASP
A
139
−11.077
39.441
31.582
0.50
20.56
O
ATOM
448
C
ASP
A
139
−13.343
36.319
31.435
1.00
28.35
C
ATOM
449
O
ASP
A
139
−12.247
36.500
30.876
1.00
29.04
O
ATOM
450
N
ARG
A
140
−13.949
35.142
31.450
1.00
28.71
N
ATOM
451
CA
ARG
A
140
−13.370
33.986
30.757
1.00
30.54
C
ATOM
452
CB
ARG
A
140
−12.409
33.226
31.674
1.00
31.65
C
ATOM
453
CG
ARG
A
140
−13.182
32.536
32.786
1.00
35.69
C
ATOM
454
CD
ARG
A
140
−12.363
31.446
33.453
1.00
41.63
C
ATOM
455
NE
ARG
A
140
−12.991
31.094
34.722
1.00
45.91
N
ATOM
456
CZ
ARG
A
140
−13.998
30.238
34.861
1.00
49.56
C
ATOM
457
NH1
ARG
A
140
−14.524
29.612
33.793
1.00
48.61
N
ATOM
458
NH2
ARG
A
140
−14.475
30.001
36.082
1.00
49.00
N
ATOM
459
C
ARG
A
140
−14.482
33.073
30.279
1.00
29.51
C
ATOM
460
O
ARG
A
140
−15.596
33.103
30.785
1.00
30.10
O
ATOM
461
N
LEU
A
141
−14.182
32.268
29.264
1.00
30.56
N
ATOM
462
CA
LEU
A
141
−15.155
31.290
28.753
1.00
29.62
C
ATOM
463
CB
LEU
A
141
−14.496
30.410
27.659
1.00
29.02
C
ATOM
464
CG
LEU
A
141
−15.359
29.328
27.005
1.00
30.21
C
ATOM
465
CD1
LEU
A
141
−14.998
29.213
25.514
1.00
25.61
C
ATOM
466
CD2
LEU
A
141
−15.146
27.989
27.689
1.00
28.22
C
ATOM
467
C
LEU
A
141
−15.579
30.396
29.907
1.00
29.31
C
ATOM
468
O
LEU
A
141
−14.754
29.975
30.687
1.00
29.67
O
ATOM
469
N
GLU
A
142
−16.862
30.108
29.994
1.00
28.07
N
ATOM
470
CA
GLU
A
142
−17.352
29.241
31.047
1.00
28.71
C
ATOM
471
CB
GLU
A
142
−18.590
29.848
31.667
1.00
29.55
C
ATOM
472
CG
GLU
A
142
−19.167
28.964
32.766
1.00
32.35
C
ATOM
473
CD
GLU
A
142
−20.382
29.575
33.338
1.00
38.85
C
ATOM
474
OE1
GLU
A
142
−20.438
29.665
34.586
1.00
43.19
O
ATOM
475
OE2
GLU
A
142
−21.250
30.017
32.550
1.00
42.00
O
ATOM
476
C
GLU
A
142
−17.759
27.888
30.468
1.00
27.92
C
ATOM
477
O
GLU
A
142
−17.164
26.875
30.802
1.00
28.27
O
ATOM
478
N
THR
A
143
−18.763
27.910
29.593
1.00
27.95
N
ATOM
479
CA
THR
A
143
−19.305
26.688
28.986
1.00
28.53
C
ATOM
480
CB
THR
A
143
−20.710
26.388
29.572
1.00
28.46
C
ATOM
481
OG1
THR
A
143
−20.565
26.177
30.990
1.00
30.36
O
ATOM
482
CG2
THR
A
143
−21.331
25.138
28.946
1.00
32.14
C
ATOM
483
C
THR
A
143
−19.370
26.837
27.462
1.00
27.05
C
ATOM
484
O
THR
A
143
−20.027
27.702
26.949
1.00
28.79
O
ATOM
485
N
LEU
A
144
−18.719
25.950
26.736
1.00
26.74
N
ATOM
486
CA
LEU
A
144
−18.790
25.988
25.263
1.00
23.71
C
ATOM
487
CB
LEU
A
144
−17.608
25.189
24.712
1.00
23.74
C
ATOM
488
CG
LEU
A
144
−17.563
25.142
23.164
1.00
23.31
C
ATOM
489
CD1
LEU
A
144
−17.213
26.514
22.590
1.00
23.32
C
ATOM
490
CD2
LEU
A
144
−16.567
24.119
22.730
1.00
22.22
C
ATOM
491
C
LEU
A
144
−20.119
25.426
24.797
1.00
24.71
C
ATOM
492
O
LEU
A
144
−20.529
24.338
25.242
1.00
24.35
O
ATOM
493
N
ILE
A
145
−20.821
26.133
23.923
1.00
23.45
N
ATOM
494
CA
ILE
A
145
−21.970
25.538
23.265
1.00
25.19
C
ATOM
495
CB
ILE
A
145
−23.055
26.592
23.018
1.00
25.84
C
ATOM
496
CG1
ILE
A
145
−23.640
27.052
24.388
1.00
30.13
C
ATOM
497
CD1
ILE
A
145
−24.255
28.496
24.272
1.00
38.82
C
ATOM
498
CG2
ILE
A
145
−24.150
26.089
22.057
1.00
26.97
C
ATOM
499
C
ILE
A
145
−21.515
24.854
21.938
1.00
25.87
C
ATOM
500
O
ILE
A
145
−21.817
23.679
21.687
1.00
23.59
O
ATOM
501
N
LEU
A
146
−20.772
25.593
21.112
1.00
25.26
N
ATOM
502
CA
LEU
A
146
−20.211
24.985
19.893
1.00
23.95
C
ATOM
503
CB
LEU
A
146
−21.302
24.942
18.833
1.00
23.73
C
ATOM
504
CG
LEU
A
146
−21.016
24.183
17.505
1.00
24.90
C
ATOM
505
CD1
LEU
A
146
−20.763
22.691
17.791
1.00
25.12
C
ATOM
506
CD2
LEU
A
146
−22.185
24.339
16.580
1.00
24.67
C
ATOM
507
C
LEU
A
146
−19.118
25.874
19.383
1.00
23.11
C
ATOM
508
O
LEU
A
146
−19.292
27.130
19.424
1.00
22.17
O
ATOM
509
N
LEU
A
147
−18.034
25.281
18.835
1.00
22.70
N
ATOM
510
CA
LEU
A
147
−17.008
26.058
18.122
1.00
21.78
C
ATOM
511
CB
LEU
A
147
−15.647
25.947
18.857
1.00
22.68
C
ATOM
512
CG
LEU
A
147
−14.450
26.653
18.206
1.00
22.20
C
ATOM
513
CD1
LEU
A
147
−13.385
27.062
19.271
1.00
20.77
C
ATOM
514
CD2
LEU
A
147
−13.814
25.775
17.088
1.00
19.37
C
ATOM
515
C
LEU
A
147
−16.907
25.455
16.717
1.00
22.57
C
ATOM
516
O
LEU
A
147
−16.910
24.212
16.593
1.00
20.70
O
ATOM
517
N
ARG
A
148
−16.848
26.293
15.663
1.00
22.59
N
ATOM
518
CA
ARG
A
148
−16.671
25.730
14.283
1.00
23.35
C
ATOM
519
CB
ARG
A
148
−17.969
25.749
13.455
1.00
22.58
C
ATOM
520
CG
ARG
A
148
−18.861
24.593
13.818
1.00
23.66
C
ATOM
521
CD
ARG
A
148
−20.240
24.671
13.269
1.00
23.87
C
ATOM
522
NE
ARG
A
148
−20.804
23.336
13.367
1.00
23.59
N
ATOM
523
CZ
ARG
A
148
−22.035
22.980
12.978
1.00
25.11
C
ATOM
524
NH1
ARG
A
148
−22.902
23.870
12.516
1.00
22.41
N
ATOM
525
NH2
ARG
A
148
−22.395
21.722
13.079
1.00
22.69
N
ATOM
526
C
ARG
A
148
−15.582
26.490
13.594
1.00
23.50
C
ATOM
527
O
ARG
A
148
−15.329
27.665
13.935
1.00
23.78
O
ATOM
528
N
ALA
A
149
−14.904
25.785
12.696
1.00
23.63
N
ATOM
529
CA
ALA
A
149
−13.834
26.339
11.887
1.00
22.68
C
ATOM
530
CB
ALA
A
149
−12.672
25.334
11.840
1.00
21.04
C
ATOM
531
C
ALA
A
149
−14.403
26.626
10.477
1.00
23.39
C
ATOM
532
O
ALA
A
149
−14.904
25.710
9.830
1.00
22.23
O
ATOM
533
N
PHE
A
150
−14.330
27.903
10.033
1.00
23.42
N
ATOM
534
CA
PHE
A
150
−14.947
28.333
8.761
1.00
24.77
C
ATOM
535
CB
PHE
A
150
−15.867
29.532
9.015
1.00
24.60
C
ATOM
536
CG
PHE
A
150
−17.135
29.184
9.792
1.00
26.17
C
ATOM
537
CD1
PHE
A
150
−17.133
29.193
11.188
1.00
25.87
C
ATOM
538
CE1
PHE
A
150
−18.268
28.861
11.919
1.00
27.48
C
ATOM
539
CZ
PHE
A
150
−19.440
28.542
11.266
1.00
25.00
C
ATOM
540
CE2
PHE
A
150
−19.474
28.526
9.862
1.00
26.61
C
ATOM
541
CD2
PHE
A
150
−18.288
28.825
9.124
1.00
25.13
C
ATOM
542
C
PHE
A
150
−13.895
28.796
7.717
1.00
24.98
C
ATOM
543
O
PHE
A
150
−12.963
29.457
8.072
1.00
24.09
O
ATOM
544
N
THR
A
151
−14.067
28.444
6.438
1.00
27.78
N
ATOM
545
CA
THR
A
151
−13.220
28.983
5.382
1.00
29.28
C
ATOM
546
CB
THR
A
151
−13.312
28.158
4.077
1.00
28.87
C
ATOM
547
OG1
THR
A
151
−14.613
28.302
3.542
1.00
29.93
O
ATOM
548
CG2
THR
A
151
−13.106
26.674
4.323
1.00
29.18
C
ATOM
549
C
THR
A
151
−13.743
30.414
5.115
1.00
31.10
C
ATOM
550
O
THR
A
151
−14.779
30.810
5.628
1.00
29.33
O
ATOM
551
N
GLU
A
152
−13.033
31.168
4.282
1.00
33.68
N
ATOM
552
CA
GLU
A
152
−13.425
32.530
3.902
1.00
36.84
C
ATOM
553
CB
GLU
A
152
−12.347
33.131
2.999
1.00
37.30
C
ATOM
554
CG
GLU
A
152
−11.005
33.248
3.642
1.00
39.17
C
ATOM
555
CD
GLU
A
152
−10.026
34.031
2.777
1.00
48.59
C
ATOM
556
OE1
GLU
A
152
−9.561
33.489
1.748
1.00
51.49
O
ATOM
557
OE2
GLU
A
152
−9.735
35.191
3.123
1.00
49.86
O
ATOM
558
C
GLU
A
152
−14.765
32.567
3.170
1.00
37.80
C
ATOM
559
O
GLU
A
152
−15.468
33.595
3.173
1.00
39.18
O
ATOM
560
N
GLU
A
153
−15.098
31.444
2.547
1.00
38.19
N
ATOM
561
CA
GLU
A
153
−16.337
31.296
1.834
1.00
39.91
C
ATOM
562
CB
GLU
A
153
−16.145
30.349
0.633
1.00
41.25
C
ATOM
563
CG
GLU
A
153
−15.204
30.939
−0.498
1.00
47.72
C
ATOM
564
CD
GLU
A
153
−15.857
32.067
−1.366
1.00
56.46
C
ATOM
565
OE1
GLU
A
153
−17.009
32.489
−1.073
1.00
59.59
O
ATOM
566
OE2
GLU
A
153
−15.213
32.532
−2.361
1.00
59.71
O
ATOM
567
C
GLU
A
153
−17.466
30.825
2.747
1.00
39.18
C
ATOM
568
O
GLU
A
153
−18.595
30.594
2.283
1.00
40.28
O
ATOM
569
N
GLY
A
154
−17.183
30.645
4.037
1.00
36.32
N
ATOM
570
CA
GLY
A
154
−18.270
30.319
4.947
1.00
33.51
C
ATOM
571
C
GLY
A
154
−18.506
28.837
5.178
1.00
31.90
C
ATOM
572
O
GLY
A
154
−19.430
28.472
5.925
1.00
31.26
O
ATOM
573
N
ALA
A
155
−17.682
27.983
4.576
1.00
29.65
N
ATOM
574
CA
ALA
A
155
−17.837
26.524
4.714
1.00
28.90
C
ATOM
575
CB
ALA
A
155
−17.137
25.812
3.566
1.00
28.42
C
ATOM
576
C
ALA
A
155
−17.242
26.021
6.058
1.00
27.62
C
ATOM
577
O
ALA
A
155
−16.182
26.465
6.447
1.00
27.58
O
ATOM
578
N
ILE
A
156
−17.872
25.034
6.677
1.00
26.27
N
ATOM
579
CA
ILE
A
156
−17.329
24.438
7.943
1.00
25.83
C
ATOM
580
CB
ILE
A
156
−18.495
23.902
8.878
1.00
24.89
C
ATOM
581
CG1
ILE
A
156
−19.502
25.006
9.143
1.00
25.36
C
ATOM
582
CD1
ILE
A
156
−20.917
24.545
9.521
1.00
25.07
C
ATOM
583
CG2
ILE
A
156
−17.916
23.352
10.265
1.00
24.02
C
ATOM
584
C
ILE
A
156
−16.376
23.290
7.644
1.00
25.13
C
ATOM
585
O
ILE
A
156
−16.737
22.408
6.867
1.00
25.16
O
ATOM
586
N
VAL
A
157
−15.170
23.316
8.241
1.00
24.13
N
ATOM
587
CA
VAL
A
157
−14.131
22.283
8.038
1.00
24.32
C
ATOM
588
CB
VAL
A
157
−12.963
22.870
7.253
1.00
24.35
C
ATOM
589
CG1
VAL
A
157
−13.491
23.401
5.896
1.00
24.56
C
ATOM
590
CG2
VAL
A
157
−12.253
24.009
8.052
1.00
23.30
C
ATOM
591
C
VAL
A
157
−13.643
21.653
9.369
1.00
24.38
C
ATOM
592
O
VAL
A
157
−12.742
20.787
9.381
1.00
24.39
O
ATOM
593
N
GLY
A
158
−14.280
22.055
10.480
1.00
22.71
N
ATOM
594
CA
GLY
A
158
−13.817
21.558
11.800
1.00
22.42
C
ATOM
595
C
GLY
A
158
−14.768
22.001
12.869
1.00
22.76
C
ATOM
596
O
GLY
A
158
−15.476
22.988
12.689
1.00
22.09
O
ATOM
597
N
GLU
A
159
−14.778
21.272
13.985
1.00
22.77
N
ATOM
598
CA
GLU
A
159
−15.685
21.643
15.055
1.00
23.62
C
ATOM
599
CB
GLU
A
159
−17.076
21.080
14.702
1.00
23.86
C
ATOM
600
CG
GLU
A
159
−18.105
20.927
15.738
1.00
27.75
C
ATOM
601
CD
GLU
A
159
−19.298
20.220
15.110
1.00
30.96
C
ATOM
602
OE1
GLU
A
159
−19.649
19.085
15.511
1.00
33.41
O
ATOM
603
OE2
GLU
A
159
−19.793
20.784
14.126
1.00
31.84
O
ATOM
604
C
GLU
A
159
−15.224
21.096
16.400
1.00
23.45
C
ATOM
605
O
GLU
A
159
−14.503
20.083
16.451
1.00
23.41
O
ATOM
606
N
ILE
A
160
−15.623
21.803
17.461
1.00
21.90
N
ATOM
607
CA
ILE
A
160
−15.490
21.267
18.833
1.00
22.61
C
ATOM
608
CB
ILE
A
160
−14.472
21.994
19.660
1.00
22.90
C
ATOM
609
CG1
ILE
A
160
−13.072
21.846
19.064
1.00
20.56
C
ATOM
610
CD1
ILE
A
160
−12.068
22.911
19.659
1.00
23.51
C
ATOM
611
CG2
ILE
A
160
−14.473
21.422
21.160
1.00
20.30
C
ATOM
612
C
ILE
A
160
−16.868
21.407
19.432
1.00
23.34
C
ATOM
613
O
ILE
A
160
−17.471
22.524
19.438
1.00
21.20
O
ATOM
614
N
SER
A
161
−17.418
20.269
19.860
1.00
25.69
N
ATOM
615
CA
SER
A
161
−18.758
20.307
20.418
1.00
28.95
C
ATOM
616
CB
SER
A
161
−19.773
19.669
19.476
1.00
30.16
C
ATOM
617
OG
SER
A
161
−19.433
18.304
19.310
1.00
36.69
O
ATOM
618
C
SER
A
161
−18.770
19.573
21.739
1.00
31.31
C
ATOM
619
O
SER
A
161
−18.092
18.550
21.879
1.00
32.13
O
ATOM
620
N
PRO
A
162
−19.565
20.074
22.721
1.00
32.42
N
ATOM
621
CA
PRO
A
162
−19.717
19.308
23.967
1.00
32.99
C
ATOM
622
CB
PRO
A
162
−20.635
20.208
24.823
1.00
33.01
C
ATOM
623
CG
PRO
A
162
−21.460
21.013
23.754
1.00
34.38
C
ATOM
624
CD
PRO
A
162
−20.382
21.303
22.712
1.00
31.98
C
ATOM
625
C
PRO
A
162
−20.416
17.973
23.669
1.00
34.31
C
ATOM
626
O
PRO
A
162
−21.251
17.896
22.770
1.00
33.06
O
ATOM
627
N
LEU
A
163
−20.094
16.942
24.424
1.00
35.01
N
ATOM
628
CA
LEU
A
163
−20.872
15.726
24.360
1.00
39.63
C
ATOM
629
CB
LEU
A
163
−20.148
14.628
25.128
1.00
37.49
C
ATOM
630
CG
LEU
A
163
−18.770
14.289
24.594
1.00
38.56
C
ATOM
631
CD1
LEU
A
163
−18.110
13.411
25.596
1.00
42.42
C
ATOM
632
CD2
LEU
A
163
−18.870
13.613
23.197
1.00
37.70
C
ATOM
633
C
LEU
A
163
−22.287
15.986
24.964
1.00
43.24
C
ATOM
634
O
LEU
A
163
−22.429
16.761
25.922
1.00
42.85
O
ATOM
635
N
PRO
A
164
−23.329
15.347
24.407
1.00
47.70
N
ATOM
636
CA
PRO
A
164
−24.713
15.544
24.904
1.00
50.86
C
ATOM
637
CB
PRO
A
164
−25.488
14.431
24.216
1.00
50.96
C
ATOM
638
CG
PRO
A
164
−24.731
14.153
22.964
1.00
50.70
C
ATOM
639
CD
PRO
A
164
−23.272
14.390
23.288
1.00
48.08
C
ATOM
640
C
PRO
A
164
−24.778
15.330
26.404
1.00
53.85
C
ATOM
641
O
PRO
A
164
−25.371
16.133
27.144
1.00
55.14
O
ATOM
642
N
SER
A
165
−24.109
14.268
26.836
1.00
56.89
N
ATOM
643
CA
SER
A
165
−24.161
13.771
28.201
1.00
59.40
C
ATOM
644
CB
SER
A
165
−23.132
12.627
28.372
1.00
59.96
C
ATOM
645
OG
SER
A
165
−22.736
11.981
27.151
1.00
61.14
O
ATOM
646
C
SER
A
165
−23.886
14.862
29.261
1.00
60.68
C
ATOM
647
O
SER
A
165
−24.578
14.937
30.285
1.00
61.29
O
ATOM
648
N
PHE
A
166
−22.862
15.683
29.014
1.00
61.57
N
ATOM
649
CA
PHE
A
166
−22.397
16.669
29.980
1.00
61.86
C
ATOM
650
CB
PHE
A
166
−20.878
16.850
29.924
1.00
62.01
C
ATOM
651
CG
PHE
A
166
−20.108
15.569
29.780
1.00
62.40
C
ATOM
652
CD1
PHE
A
166
−19.110
15.241
30.690
1.00
63.33
C
ATOM
653
CE1
PHE
A
166
−18.373
14.035
30.563
1.00
65.13
C
ATOM
654
CZ
PHE
A
166
−18.651
13.167
29.514
1.00
64.22
C
ATOM
655
CE2
PHE
A
166
−19.666
13.493
28.597
1.00
64.14
C
ATOM
656
CD2
PHE
A
166
−20.371
14.691
28.729
1.00
62.88
C
ATOM
657
C
PHE
A
166
−23.042
18.021
29.748
1.00
62.36
C
ATOM
658
O
PHE
A
166
−23.417
18.368
28.598
1.00
62.89
O
ATOM
659
N
PRO
A
167
−23.210
18.775
30.845
1.00
62.06
N
ATOM
660
CA
PRO
A
167
−23.394
20.224
30.872
1.00
61.87
C
ATOM
661
CB
PRO
A
167
−24.570
20.379
31.857
1.00
61.66
C
ATOM
662
CG
PRO
A
167
−24.317
19.276
32.881
1.00
62.79
C
ATOM
663
CD
PRO
A
167
−23.353
18.232
32.208
1.00
62.77
C
ATOM
664
C
PRO
A
167
−22.130
20.921
31.431
1.00
60.38
C
ATOM
665
O
PRO
A
167
−22.154
22.141
31.695
1.00
61.90
O
ATOM
666
N
GLY
A
168
−21.050
20.148
31.606
1.00
57.49
N
ATOM
667
CA
GLY
A
168
−19.868
20.625
32.321
1.00
53.21
C
ATOM
668
C
GLY
A
168
−18.504
20.149
31.843
1.00
49.27
C
ATOM
669
O
GLY
A
168
−18.198
18.926
31.777
1.00
49.67
O
ATOM
670
N
HIS
A
169
−17.681
21.149
31.549
1.00
44.84
N
ATOM
671
CA
HIS
A
169
−16.297
20.976
31.148
1.00
40.46
C
ATOM
672
CB
HIS
A
169
−16.170
20.820
29.602
1.00
38.65
C
ATOM
673
CG
HIS
A
169
−16.962
21.841
28.822
1.00
33.52
C
ATOM
674
ND1
HIS
A
169
−18.188
21.564
28.261
1.00
31.35
N
ATOM
675
CE1
HIS
A
169
−18.660
22.637
27.660
1.00
28.39
C
ATOM
676
NE2
HIS
A
169
−17.796
23.616
27.828
1.00
28.28
N
ATOM
677
CD2
HIS
A
169
−16.724
23.149
28.553
1.00
30.88
C
ATOM
678
C
HIS
A
169
−15.680
22.280
31.615
1.00
39.31
C
ATOM
679
O
HIS
A
169
−16.410
23.196
32.044
1.00
40.25
O
ATOM
680
N
THR
A
170
−14.353
22.339
31.567
1.00
36.78
N
ATOM
681
CA
THR
A
170
−13.572
23.479
32.029
1.00
35.94
C
ATOM
682
CB
THR
A
170
−12.377
23.065
32.927
1.00
35.25
C
ATOM
683
OG1
THR
A
170
−11.388
22.393
32.139
1.00
34.72
O
ATOM
684
CG2
THR
A
170
−12.827
22.132
34.101
1.00
36.64
C
ATOM
685
C
THR
A
170
−13.000
24.216
30.823
1.00
35.21
C
ATOM
686
O
THR
A
170
−12.946
23.678
29.710
1.00
34.35
O
ATOM
687
N
ILE
A
171
−12.568
25.444
31.058
1.00
33.91
N
ATOM
688
CA
ILE
A
171
−11.914
26.233
30.027
1.00
33.18
C
ATOM
689
CB
ILE
A
171
−11.670
27.696
30.532
1.00
32.72
C
ATOM
690
CG1
ILE
A
171
−11.151
28.586
29.382
1.00
33.82
C
ATOM
691
CD1
ILE
A
171
−11.256
30.068
29.689
1.00
32.91
C
ATOM
692
CG2
ILE
A
171
−10.725
27.732
31.733
1.00
33.57
C
ATOM
693
C
ILE
A
171
−10.620
25.547
29.575
1.00
32.14
C
ATOM
694
O
ILE
A
171
−10.221
25.637
28.412
1.00
31.34
O
ATOM
695
N
GLU
A
172
−9.965
24.841
30.492
1.00
31.90
N
ATOM
696
CA
GLU
A
172
−8.761
24.099
30.150
1.00
32.76
C
ATOM
697
CB
GLU
A
172
−8.014
23.596
31.399
1.00
33.50
C
ATOM
698
CG
GLU
A
172
−7.752
24.691
32.487
1.00
38.99
C
ATOM
699
CD
GLU
A
172
−8.749
24.570
33.660
1.00
46.04
C
ATOM
700
OE1
GLU
A
172
−8.553
23.659
34.517
1.00
53.70
O
ATOM
701
OE2
GLU
A
172
−9.725
25.351
33.744
1.00
48.14
O
ATOM
702
C
GLU
A
172
−9.055
22.916
29.185
1.00
31.70
C
ATOM
703
O
GLU
A
172
−8.256
22.649
28.286
1.00
31.20
O
ATOM
704
N
ASP
A
173
−10.171
22.207
29.399
1.00
31.31
N
ATOM
705
CA
ASP
A
173
−10.650
21.204
28.408
1.00
30.63
C
ATOM
706
CB
ASP
A
173
−12.011
20.603
28.808
1.00
29.29
C
ATOM
707
CG
ASP
A
173
−11.929
19.745
30.069
1.00
32.36
C
ATOM
708
OD1
ASP
A
173
−10.912
19.089
30.317
1.00
36.48
O
ATOM
709
OD2
ASP
A
173
−12.885
19.746
30.820
1.00
29.46
O
ATOM
710
C
ASP
A
173
−10.859
21.898
27.049
1.00
29.18
C
ATOM
711
O
ASP
A
173
−10.512
21.341
25.994
1.00
28.08
O
ATOM
712
N
VAL
A
174
−11.483
23.071
27.081
1.00
27.66
N
ATOM
713
CA
VAL
A
174
−11.768
23.785
25.829
1.00
27.50
C
ATOM
714
CB
VAL
A
174
−12.677
25.024
26.047
1.00
28.13
C
ATOM
715
CG1
VAL
A
174
−12.760
25.860
24.766
1.00
27.42
C
ATOM
716
CG2
VAL
A
174
−14.062
24.576
26.464
1.00
26.02
C
ATOM
717
C
VAL
A
174
−10.459
24.167
25.150
1.00
28.12
C
ATOM
718
O
VAL
A
174
−10.288
23.952
23.912
1.00
26.80
O
ATOM
719
N
LYS
A
175
−9.517
24.720
25.913
1.00
27.32
N
ATOM
720
CA
LYS
A
175
−8.229
25.090
25.333
1.00
29.37
C
ATOM
721
CB
LYS
A
175
−7.336
25.851
26.319
1.00
29.49
C
ATOM
722
CG
LYS
A
175
−7.873
27.277
26.719
1.00
31.65
C
ATOM
723
CD
LYS
A
175
−7.042
27.779
27.947
1.00
34.24
C
ATOM
724
CE
LYS
A
175
−6.548
29.216
27.757
1.00
43.77
C
ATOM
725
NZ
LYS
A
175
−5.086
29.241
28.061
1.00
49.63
N
ATOM
726
C
LYS
A
175
−7.475
23.894
24.764
1.00
29.15
C
ATOM
727
O
LYS
A
175
−6.905
23.989
23.676
1.00
29.98
O
ATOM
728
N
ASN
A
176
−7.464
22.772
25.485
1.00
28.78
N
ATOM
729
CA
ASN
A
176
−6.806
21.577
24.971
1.00
29.56
C
ATOM
730
CB
ASN
A
176
−7.002
20.378
25.906
1.00
29.89
C
ATOM
731
CG
ASN
A
176
−6.190
20.483
27.181
1.00
37.18
C
ATOM
732
OD1
ASN
A
176
−6.501
19.795
28.175
1.00
42.17
O
ATOM
733
ND2
ASN
A
176
−5.141
21.338
27.178
1.00
41.19
N
ATOM
734
C
ASN
A
176
−7.387
21.203
23.614
1.00
27.60
C
ATOM
735
O
ASN
A
176
−6.648
20.894
22.683
1.00
27.59
O
ATOM
736
N
ALA
A
177
−8.705
21.202
23.527
1.00
25.47
N
ATOM
737
CA
ALA
A
177
−9.386
20.816
22.292
1.00
25.42
C
ATOM
738
CB
ALA
A
177
−10.899
20.715
22.505
1.00
23.91
C
ATOM
739
C
ALA
A
177
−9.070
21.744
21.148
1.00
24.79
C
ATOM
740
O
ALA
A
177
−8.944
21.266
20.001
1.00
25.02
O
ATOM
741
N
ILE
A
178
−9.013
23.060
21.440
1.00
23.30
N
ATOM
742
CA
ILE
A
178
−8.731
24.063
20.464
1.00
24.16
C
ATOM
743
CB
ILE
A
178
−8.883
25.496
21.039
1.00
23.64
C
ATOM
744
CG1
ILE
A
178
−10.344
25.862
21.218
1.00
23.43
C
ATOM
745
CD1
ILE
A
178
−10.566
27.275
21.940
1.00
24.62
C
ATOM
746
CG2
ILE
A
178
−8.167
26.518
20.104
1.00
24.53
C
ATOM
747
C
ILE
A
178
−7.307
23.869
19.924
1.00
25.28
C
ATOM
748
O
ILE
A
178
−7.076
23.950
18.708
1.00
23.52
O
ATOM
749
N
GLY
A
179
−6.361
23.568
20.821
1.00
25.82
N
ATOM
750
CA
GLY
A
179
−4.994
23.233
20.391
1.00
24.95
C
ATOM
751
C
GLY
A
179
−4.920
22.005
19.483
1.00
26.34
C
ATOM
752
O
GLY
A
179
−4.115
21.988
18.537
1.00
25.96
O
ATOM
753
N
VAL
A
180
−5.757
20.999
19.713
1.00
25.94
N
ATOM
754
CA
VAL
A
180
−5.748
19.794
18.840
1.00
27.50
C
ATOM
755
CB
VAL
A
180
−6.549
18.632
19.443
1.00
28.63
C
ATOM
756
CG1
VAL
A
180
−6.696
17.436
18.427
1.00
30.08
C
ATOM
757
CG2
VAL
A
180
−5.898
18.139
20.725
1.00
29.50
C
ATOM
758
C
VAL
A
180
−6.301
20.114
17.428
1.00
27.72
C
ATOM
759
O
VAL
A
180
−5.723
19.737
16.403
1.00
27.57
O
ATOM
760
N
LEU
A
181
−7.435
20.811
17.415
1.00
26.46
N
ATOM
761
CA
LEU
A
181
−8.043
21.334
16.195
1.00
26.40
C
ATOM
762
CB
LEU
A
181
−9.400
22.036
16.521
1.00
25.50
C
ATOM
763
CG
LEU
A
181
−10.103
22.583
15.258
1.00
25.35
C
ATOM
764
CD1
LEU
A
181
−10.370
21.411
14.239
1.00
23.23
C
ATOM
765
CD2
LEU
A
181
−11.377
23.348
15.605
1.00
25.48
C
ATOM
766
C
LEU
A
181
−7.092
22.262
15.412
1.00
25.60
C
ATOM
767
O
LEU
A
181
−6.849
22.045
14.207
1.00
23.63
O
ATOM
768
N
ILE
A
182
−6.577
23.300
16.058
1.00
24.97
N
ATOM
769
CA
ILE
A
182
−5.652
24.214
15.375
1.00
26.01
C
ATOM
770
CB
ILE
A
182
−5.196
25.420
16.291
1.00
26.44
C
ATOM
771
CG1
ILE
A
182
−6.341
26.404
16.468
1.00
26.81
C
ATOM
772
CD1
ILE
A
182
−6.078
27.572
17.483
1.00
25.50
C
ATOM
773
CG2
ILE
A
182
−4.006
26.171
15.657
1.00
26.76
C
ATOM
774
C
ILE
A
182
−4.401
23.498
14.849
1.00
27.06
C
ATOM
775
O
ILE
A
182
−3.903
23.798
13.737
1.00
27.99
O
ATOM
776
N
GLY
A
183
−3.903
22.544
15.625
1.00
26.95
N
ATOM
777
CA
GLY
A
183
−2.733
21.763
15.236
1.00
27.09
C
ATOM
778
C
GLY
A
183
−2.939
20.942
13.966
1.00
27.16
C
ATOM
779
O
GLY
A
183
−2.035
20.852
13.118
1.00
25.04
O
ATOM
780
N
GLY
A
184
−4.143
20.391
13.798
1.00
26.79
N
ATOM
781
CA
GLY
A
184
−4.454
19.527
12.642
1.00
26.69
C
ATOM
782
C
GLY
A
184
−4.633
20.410
11.450
1.00
26.33
C
ATOM
783
O
GLY
A
184
−4.127
20.120
10.380
1.00
26.17
O
ATOM
784
N
LEU
A
185
−5.313
21.534
11.638
1.00
26.30
N
ATOM
785
CA
LEU
A
185
−5.499
22.492
10.565
1.00
24.55
C
ATOM
786
CB
LEU
A
185
−6.415
23.616
11.001
1.00
23.84
C
ATOM
787
CG
LEU
A
185
−7.888
23.220
11.293
1.00
23.68
C
ATOM
788
CD1
LEU
A
185
−8.599
24.422
12.020
1.00
23.04
C
ATOM
789
CD2
LEU
A
185
−8.559
22.845
9.959
1.00
21.51
C
ATOM
790
C
LEU
A
185
−4.175
23.072
10.089
1.00
26.07
C
ATOM
791
O
LEU
A
185
−3.967
23.195
8.863
1.00
24.84
O
ATOM
792
N
GLU
A
186
−3.320
23.489
11.021
1.00
24.68
N
ATOM
793
CA
GLU
A
186
−1.974
24.029
10.643
1.00
26.89
C
ATOM
794
CB
GLU
A
186
−1.271
24.702
11.828
1.00
26.28
C
ATOM
795
CG
GLU
A
186
−1.956
25.957
12.224
1.00
29.68
C
ATOM
796
CD
GLU
A
186
−1.329
26.627
13.460
1.00
30.75
C
ATOM
797
OE1
GLU
A
186
−0.559
25.977
14.192
1.00
36.73
O
ATOM
798
OE2
GLU
A
186
−1.625
27.804
13.670
1.00
33.71
O
ATOM
799
C
GLU
A
186
−1.046
23.007
10.020
1.00
27.78
C
ATOM
800
O
GLU
A
186
−0.236
23.366
9.102
1.00
28.87
O
ATOM
801
N
TRP
A
187
−1.120
21.762
10.495
1.00
29.22
N
ATOM
802
CA
TRP
A
187
−0.402
20.622
9.874
1.00
30.02
C
ATOM
803
CB
TRP
A
187
−0.669
19.278
10.586
1.00
31.40
C
ATOM
804
CG
TRP
A
187
−0.339
17.955
9.756
1.00
33.36
C
ATOM
805
CD1
TRP
A
187
−1.180
17.266
8.885
1.00
36.81
C
ATOM
806
NE1
TRP
A
187
−0.563
16.136
8.391
1.00
37.42
N
ATOM
807
CE2
TRP
A
187
0.699
16.083
8.919
1.00
38.06
C
ATOM
808
CD2
TRP
A
187
0.869
17.200
9.788
1.00
35.93
C
ATOM
809
CE3
TRP
A
187
2.079
17.363
10.464
1.00
35.96
C
ATOM
810
CZ3
TRP
A
187
3.041
16.448
10.268
1.00
38.27
C
ATOM
811
CH2
TRP
A
187
2.857
15.350
9.386
1.00
37.53
C
ATOM
812
CZ2
TRP
A
187
1.676
15.149
8.721
1.00
36.20
C
ATOM
813
C
TRP
A
187
−0.753
20.517
8.387
1.00
29.83
C
ATOM
814
O
TRP
A
187
0.135
20.246
7.539
1.00
27.61
O
ATOM
815
N
ASN
A
188
−2.037
20.751
8.078
1.00
28.16
N
ATOM
816
CA
ASN
A
188
−2.521
20.755
6.679
1.00
28.81
C
ATOM
817
CB
ASN
A
188
−4.018
20.335
6.628
1.00
27.28
C
ATOM
818
CG
ASN
A
188
−4.189
18.844
6.447
1.00
27.85
C
ATOM
819
OD1
ASN
A
188
−3.221
18.120
6.229
1.00
30.13
O
ATOM
820
ND2
ASN
A
188
−5.416
18.367
6.562
1.00
25.16
N
ATOM
821
C
ASN
A
188
−2.317
22.083
5.939
1.00
28.69
C
ATOM
822
O
ASN
A
188
−2.976
22.351
4.912
1.00
28.16
O
ATOM
823
N
ASP
A
189
−1.417
22.916
6.453
1.00
28.38
N
ATOM
824
CA
ASP
A
189
−1.064
24.186
5.841
1.00
29.63
C
ATOM
825
CB
ASP
A
189
−0.361
23.927
4.472
1.00
30.44
C
ATOM
826
CG
ASP
A
189
0.978
23.255
4.654
1.00
34.49
C
ATOM
827
OD1
ASP
A
189
1.747
23.745
5.545
1.00
36.20
O
ATOM
828
OD2
ASP
A
189
1.210
22.192
4.008
1.00
37.75
O
ATOM
829
C
ASP
A
189
−2.195
25.185
5.706
1.00
29.23
C
ATOM
830
O
ASP
A
189
−2.196
26.026
4.788
1.00
29.61
O
ATOM
831
N
ASN
A
190
−3.161
25.105
6.622
1.00
28.19
N
ATOM
832
CA
ASN
A
190
−4.158
26.126
6.724
1.00
27.21
C
ATOM
833
CB
ASN
A
190
−5.511
25.547
7.254
1.00
25.60
C
ATOM
834
CG
ASN
A
190
−6.073
24.485
6.339
1.00
24.16
C
ATOM
835
OD1
ASN
A
190
−6.548
24.789
5.248
1.00
25.54
O
ATOM
836
ND2
ASN
A
190
−5.995
23.233
6.751
1.00
22.44
N
ATOM
837
C
ASN
A
190
−3.634
27.215
7.618
1.00
27.62
C
ATOM
838
O
ASN
A
190
−2.931
26.923
8.583
1.00
28.53
O
ATOM
839
N
THR
A
191
−4.001
28.457
7.307
1.00
28.23
N
ATOM
840
CA
THR
A
191
−3.761
29.597
8.193
1.00
28.87
C
ATOM
841
CB
THR
A
191
−3.396
30.833
7.361
1.00
29.15
C
ATOM
842
OG1
THR
A
191
−2.188
30.538
6.652
1.00
31.36
O
ATOM
843
CG2
THR
A
191
−3.171
32.049
8.277
1.00
31.30
C
ATOM
844
C
THR
A
191
−5.006
29.843
9.099
1.00
27.84
C
ATOM
845
O
THR
A
191
−6.096
30.157
8.622
1.00
27.93
O
ATOM
846
N
VAL
A
192
−4.813
29.688
10.406
1.00
28.14
N
ATOM
847
CA
VAL
A
192
−5.905
29.719
11.400
1.00
27.77
C
ATOM
848
CB
VAL
A
192
−5.808
28.512
12.350
1.00
26.87
C
ATOM
849
CG1
VAL
A
192
−7.022
28.475
13.300
1.00
27.00
C
ATOM
850
CG2
VAL
A
192
−5.690
27.162
11.532
1.00
26.44
C
ATOM
851
C
VAL
A
192
−5.905
31.048
12.235
1.00
29.05
C
ATOM
852
O
VAL
A
192
−4.876
31.468
12.806
1.00
29.85
O
ATOM
853
N
ARG
A
193
−7.048
31.703
12.284
1.00
27.96
N
ATOM
854
CA
ARG
A
193
−7.233
32.827
13.169
1.00
29.69
C
ATOM
855
CB
ARG
A
193
−7.559
34.100
12.385
1.00
29.62
C
ATOM
856
CG
ARG
A
193
−6.444
34.579
11.482
1.00
33.74
C
ATOM
857
CD
ARG
A
193
−6.956
35.638
10.516
1.00
41.01
C
ATOM
858
NE
ARG
A
193
−5.825
36.233
9.767
1.00
50.62
N
ATOM
859
CZ
ARG
A
193
−5.238
35.718
8.668
1.00
53.47
C
ATOM
860
NH1
ARG
A
193
−5.633
34.559
8.129
1.00
54.25
N
ATOM
861
NH2
ARG
A
193
−4.234
36.372
8.095
1.00
55.59
N
ATOM
862
C
ARG
A
193
−8.438
32.451
14.049
1.00
29.25
C
ATOM
863
O
ARG
A
193
−9.275
31.619
13.660
1.00
26.12
O
ATOM
864
N
VAL
A
194
−8.523
33.085
15.219
1.00
30.07
N
ATOM
865
CA
VAL
A
194
−9.676
32.896
16.113
1.00
29.06
C
ATOM
866
CB
VAL
A
194
−9.270
32.162
17.470
1.00
31.71
C
ATOM
867
CG1
VAL
A
194
−8.265
31.013
17.189
1.00
29.70
C
ATOM
868
CG2
VAL
A
194
−8.693
33.093
18.509
1.00
29.72
C
ATOM
869
C
VAL
A
194
−10.418
34.195
16.316
1.00
28.87
C
ATOM
870
O
VAL
A
194
−9.806
35.286
16.243
1.00
27.66
O
ATOM
871
N
SER
A
195
−11.728
34.104
16.556
1.00
27.12
N
ATOM
872
CA
SER
A
195
−12.581
35.299
16.612
1.00
26.89
C
ATOM
873
CB
SER
A
195
−14.036
34.898
16.873
1.00
27.31
C
ATOM
874
OG
SER
A
195
−14.129
34.257
18.174
1.00
25.66
O
ATOM
875
C
SER
A
195
−12.115
36.220
17.747
1.00
25.66
C
ATOM
876
O
SER
A
195
−11.402
35.785
18.657
1.00
24.47
O
ATOM
877
N
LYS
A
196
−12.566
37.463
17.725
1.00
26.32
N
ATOM
878
CA
LYS
A
196
−12.108
38.399
18.767
1.00
27.97
C
ATOM
879
CB
LYS
A
196
−12.581
39.815
18.418
1.00
27.76
C
ATOM
880
CG
LYS
A
196
−11.677
40.430
17.375
1.00
34.20
C
ATOM
881
CD
LYS
A
196
−12.432
41.396
16.488
1.00
42.92
C
ATOM
882
CE
LYS
A
196
−11.522
41.909
15.355
1.00
47.63
C
ATOM
883
NZ
LYS
A
196
−10.391
42.734
15.894
1.00
49.98
N
ATOM
884
C
LYS
A
196
−12.635
37.965
20.148
1.00
27.45
C
ATOM
885
O
LYS
A
196
−11.968
38.176
21.156
1.00
27.97
O
ATOM
886
N
THR
A
197
−13.844
37.390
20.179
1.00
26.73
N
ATOM
887
CA
THR
A
197
−14.400
36.946
21.454
1.00
27.39
C
ATOM
888
CB
THR
A
197
−15.880
36.620
21.372
1.00
27.32
C
ATOM
889
OG1
THR
A
197
−16.083
35.558
20.440
1.00
28.59
O
ATOM
890
CG2
THR
A
197
−16.681
37.817
20.891
1.00
27.51
C
ATOM
891
C
THR
A
197
−13.644
35.749
21.981
1.00
27.16
C
ATOM
892
O
THR
A
197
−13.384
35.655
23.195
1.00
26.76
O
ATOM
893
N
LEU
A
198
−13.258
34.825
21.092
1.00
26.56
N
ATOM
894
CA
LEU
A
198
−12.361
33.734
21.518
1.00
26.73
C
ATOM
895
CB
LEU
A
198
−12.098
32.702
20.382
1.00
27.47
C
ATOM
896
CG
LEU
A
198
−13.233
31.710
20.187
1.00
26.53
C
ATOM
897
CD1
LEU
A
198
−12.970
30.817
18.963
1.00
29.55
C
ATOM
898
CD2
LEU
A
198
−13.370
30.815
21.453
1.00
24.14
C
ATOM
899
C
LEU
A
198
−11.034
34.250
22.063
1.00
26.63
C
ATOM
900
O
LEU
A
198
−10.534
33.728
23.060
1.00
26.63
O
ATOM
901
N
GLN
A
199
−10.459
35.262
21.421
1.00
27.02
N
ATOM
902
CA
GLN
A
199
−9.203
35.819
21.900
1.00
29.00
C
ATOM
903
CB
GLN
A
199
−8.696
36.933
20.987
1.00
29.92
C
ATOM
904
CG
GLN
A
199
−8.078
36.484
19.696
1.00
35.17
C
ATOM
905
CD
GLN
A
199
−7.910
37.677
18.755
1.00
42.65
C
ATOM
906
OE1
GLN
A
199
−7.473
38.789
19.167
1.00
43.78
O
ATOM
907
NE2
GLN
A
199
−8.321
37.487
17.512
1.00
41.52
N
ATOM
908
C
GLN
A
199
−9.405
36.416
23.278
1.00
28.53
C
ATOM
909
O
GLN
A
199
−8.591
36.225
24.191
1.00
27.18
O
ATOM
910
N
ARG
A
200
−10.498
37.155
23.408
1.00
28.92
N
ATOM
911
CA
ARG
A
200
−10.796
37.871
24.666
1.00
27.60
C
ATOM
912
CB
ARG
A
200
−12.077
38.707
24.481
1.00
28.09
C
ATOM
913
CG
ARG
A
200
−12.551
39.551
25.731
1.00
27.90
C
ATOM
914
CD
ARG
A
200
−13.718
40.446
25.377
1.00
26.48
C
ATOM
915
NE
ARG
A
200
−13.279
41.396
24.356
1.00
30.07
N
ATOM
916
CZ
ARG
A
200
−13.768
41.476
23.104
1.00
28.44
C
ATOM
917
NH1
ARG
A
200
−14.793
40.738
22.716
1.00
26.58
N
ATOM
918
NH2
ARG
A
200
−13.232
42.345
22.237
1.00
28.69
N
ATOM
919
C
ARG
A
200
−10.968
36.934
25.859
1.00
28.34
C
ATOM
920
O
ARG
A
200
−10.491
37.238
26.955
1.00
28.25
O
ATOM
921
N
PHE
A
201
−11.706
35.848
25.660
1.00
28.84
N
ATOM
922
CA
PHE
A
201
−12.244
35.004
26.738
1.00
28.86
C
ATOM
923
CB
PHE
A
201
−13.772
34.828
26.559
1.00
28.35
C
ATOM
924
CG
PHE
A
201
−14.568
36.097
26.766
1.00
25.52
C
ATOM
925
CD1
PHE
A
201
−14.554
36.770
27.997
1.00
27.82
C
ATOM
926
CE1
PHE
A
201
−15.273
37.974
28.166
1.00
27.90
C
ATOM
927
CZ
PHE
A
201
−16.034
38.498
27.120
1.00
28.95
C
ATOM
928
CE2
PHE
A
201
−16.063
37.831
25.899
1.00
27.66
C
ATOM
929
CD2
PHE
A
201
−15.319
36.623
25.735
1.00
27.72
C
ATOM
930
C
PHE
A
201
−11.563
33.627
26.884
1.00
30.86
C
ATOM
931
O
PHE
A
201
−11.721
32.964
27.915
1.00
30.47
O
ATOM
932
N
ALA
A
202
−10.780
33.200
25.895
1.00
31.85
N
ATOM
933
CA
ALA
A
202
−10.326
31.801
25.894
1.00
34.65
C
ATOM
934
CB
ALA
A
202
−11.347
30.904
25.154
1.00
32.12
C
ATOM
935
C
ALA
A
202
−8.924
31.544
25.367
1.00
37.14
C
ATOM
936
O
ALA
A
202
−8.222
30.715
25.921
1.00
38.77
O
ATOM
937
N
TRP
A
203
−8.523
32.260
24.307
1.00
38.77
N
ATOM
938
CA
TRP
A
203
−7.316
31.934
23.527
1.00
40.33
C
ATOM
939
CB
TRP
A
203
−7.720
31.335
22.174
1.00
38.58
C
ATOM
940
CG
TRP
A
203
−6.610
30.594
21.453
1.00
38.71
C
ATOM
941
CD1
TRP
A
203
−5.864
31.038
20.370
1.00
37.42
C
ATOM
942
NE1
TRP
A
203
−4.978
30.057
19.965
1.00
37.40
N
ATOM
943
CE2
TRP
A
203
−5.106
28.975
20.808
1.00
36.87
C
ATOM
944
CD2
TRP
A
203
−6.134
29.284
21.754
1.00
36.44
C
ATOM
945
CE3
TRP
A
203
−6.459
28.335
22.740
1.00
38.19
C
ATOM
946
CZ3
TRP
A
203
−5.762
27.090
22.750
1.00
37.22
C
ATOM
947
CH2
TRP
A
203
−4.749
26.813
21.786
1.00
36.78
C
ATOM
948
CZ2
TRP
A
203
−4.406
27.742
20.821
1.00
36.69
C
ATOM
949
C
TRP
A
203
−6.525
33.207
23.251
1.00
42.00
C
ATOM
950
O
TRP
A
203
−6.552
33.692
22.103
1.00
44.02
O
ATOM
951
OXT
TRP
A
203
−5.876
33.797
24.117
1.00
42.42
O
ATOM
952
N
PRO
B
85
7.442
25.386
−43.697
1.00
62.33
N
ATOM
953
CA
PRO
B
85
8.153
26.040
−42.594
1.00
61.88
C
ATOM
954
CB
PRO
B
85
7.082
26.935
−41.948
1.00
62.07
C
ATOM
955
CG
PRO
B
85
6.069
27.170
−43.026
1.00
62.66
C
ATOM
956
CD
PRO
B
85
6.075
25.911
−43.875
1.00
62.82
C
ATOM
957
C
PRO
B
85
8.678
25.031
−41.572
1.00
60.95
C
ATOM
958
O
PRO
B
85
7.988
24.045
−41.269
1.00
61.39
O
ATOM
959
N
ALA
B
86
9.893
25.269
−41.064
1.00
59.55
N
ATOM
960
CA
ALA
B
86
10.476
24.427
−40.026
1.00
58.13
C
ATOM
961
CB
ALA
B
86
11.886
24.854
−39.737
1.00
58.01
C
ATOM
962
C
ALA
B
86
9.618
24.453
−38.750
1.00
57.61
C
ATOM
963
O
ALA
B
86
8.875
25.413
−38.517
1.00
57.45
O
ATOM
964
N
SER
B
87
9.699
23.382
−37.955
1.00
56.80
N
ATOM
965
CA
SER
B
87
9.094
23.341
−36.621
1.00
55.97
C
ATOM
966
CB
SER
B
87
9.578
22.115
−35.841
1.00
56.09
C
ATOM
967
OG
SER
B
87
9.096
20.914
−36.416
1.00
59.57
O
ATOM
968
C
SER
B
87
9.504
24.568
−35.832
1.00
54.53
C
ATOM
969
O
SER
B
87
10.638
25.044
−35.952
1.00
53.79
O
ATOM
970
N
ARG
B
88
8.587
25.081
−35.022
1.00
53.11
N
ATOM
971
CA
ARG
B
88
8.994
26.013
−33.978
1.00
51.52
C
ATOM
972
CB
ARG
B
88
8.504
27.432
−34.252
1.00
52.04
C
ATOM
973
CG
ARG
B
88
7.041
27.550
−34.529
1.00
54.33
C
ATOM
974
CD
ARG
B
88
6.728
28.924
−35.062
1.00
57.93
C
ATOM
975
NE
ARG
B
88
5.363
29.328
−34.759
1.00
60.15
N
ATOM
976
CZ
ARG
B
88
5.012
30.052
−33.699
1.00
63.10
C
ATOM
977
NH1
ARG
B
88
5.932
30.458
−32.815
1.00
62.43
N
ATOM
978
NH2
ARG
B
88
3.730
30.373
−33.519
1.00
62.59
N
ATOM
979
C
ARG
B
88
8.537
25.490
−32.617
1.00
49.39
C
ATOM
980
O
ARG
B
88
7.619
24.684
−32.550
1.00
47.87
O
ATOM
981
N
TYR
B
89
9.217
25.943
−31.567
1.00
47.24
N
ATOM
982
CA
TYR
B
89
8.982
25.477
−30.204
1.00
45.49
C
ATOM
983
CB
TYR
B
89
10.298
25.132
−29.498
1.00
46.96
C
ATOM
984
CG
TYR
B
89
10.938
23.840
−29.949
1.00
49.23
C
ATOM
985
CD1
TYR
B
89
12.003
23.859
−30.844
1.00
51.93
C
ATOM
986
CE1
TYR
B
89
12.614
22.678
−31.274
1.00
53.21
C
ATOM
987
CZ
TYR
B
89
12.159
21.453
−30.800
1.00
52.97
C
ATOM
988
OH
TYR
B
89
12.793
20.295
−31.238
1.00
52.46
O
ATOM
989
CE2
TYR
B
89
11.089
21.403
−29.901
1.00
51.87
C
ATOM
990
CD2
TYR
B
89
10.485
22.596
−29.482
1.00
50.16
C
ATOM
991
C
TYR
B
89
8.251
26.525
−29.391
1.00
43.03
C
ATOM
992
O
TYR
B
89
8.599
27.718
−29.405
1.00
42.37
O
ATOM
993
N
ILE
B
90
7.230
26.066
−28.685
1.00
39.81
N
ATOM
994
CA
ILE
B
90
6.552
26.883
−27.712
1.00
37.00
C
ATOM
995
CB
ILE
B
90
5.018
26.620
−27.746
1.00
37.76
C
ATOM
996
CG1
ILE
B
90
4.414
26.837
−29.163
1.00
37.36
C
ATOM
997
CD1
ILE
B
90
4.795
28.145
−29.862
1.00
39.19
C
ATOM
998
CG2
ILE
B
90
4.317
27.434
−26.660
1.00
34.76
C
ATOM
999
C
ILE
B
90
7.120
26.456
−26.366
1.00
36.01
C
ATOM
1000
O
ILE
B
90
7.290
25.244
−26.111
1.00
34.34
O
ATOM
1001
N
THR
B
91
7.455
27.422
−25.516
1.00
35.22
N
ATOM
1002
CA
THR
B
91
8.016
27.093
−24.204
1.00
35.55
C
ATOM
1003
CB
THR
B
91
9.552
27.381
−24.113
1.00
36.05
C
ATOM
1004
OG1
THR
B
91
9.811
28.768
−24.427
1.00
37.96
O
ATOM
1005
CG2
THR
B
91
10.350
26.466
−25.020
1.00
37.46
C
ATOM
1006
C
THR
B
91
7.286
27.902
−23.156
1.00
35.72
C
ATOM
1007
O
THR
B
91
7.699
29.018
−22.827
1.00
35.37
O
ATOM
1008
N
ASP
B
92
6.161
27.373
−22.666
1.00
35.05
N
ATOM
1009
CA
ASP
B
92
5.366
28.077
−21.650
1.00
33.77
C
ATOM
1010
CB
ASP
B
92
4.034
27.364
−21.361
1.00
33.89
C
ATOM
1011
CG
ASP
B
92
2.992
27.502
−22.482
1.00
34.60
C
ATOM
1012
OD1
ASP
B
92
3.154
28.326
−23.431
1.00
35.61
O
ATOM
1013
OD2
ASP
B
92
1.975
26.774
−22.383
1.00
33.13
O
ATOM
1014
C
ASP
B
92
6.146
28.082
−20.349
1.00
33.53
C
ATOM
1015
O
ASP
B
92
6.056
29.033
−19.578
1.00
33.40
O
ATOM
1016
N
MET
B
93
6.878
27.009
−20.083
1.00
32.58
N
ATOM
1017
CA
MET
B
93
7.539
26.857
−18.794
1.00
32.30
C
ATOM
1018
CB
MET
B
93
7.607
25.369
−18.402
1.00
32.52
C
ATOM
1019
CG
MET
B
93
6.322
24.773
−17.914
1.00
29.43
C
ATOM
1020
SD
MET
B
93
6.429
23.054
−17.472
1.00
28.89
S
ATOM
1021
CE
MET
B
93
5.883
22.183
−18.940
1.00
26.92
C
ATOM
1022
C
MET
B
93
8.983
27.427
−18.831
1.00
34.01
C
ATOM
1023
O
MET
B
93
9.657
27.323
−19.864
1.00
32.66
O
ATOM
1024
N
THR
B
94
9.457
27.980
−17.704
1.00
34.20
N
ATOM
1025
CA
THR
B
94
10.880
28.311
−17.544
1.00
35.22
C
ATOM
1026
CB
THR
B
94
11.120
29.178
−16.266
1.00
36.09
C
ATOM
1027
OG1
THR
B
94
10.674
28.440
−15.134
1.00
36.40
O
ATOM
1028
CG2
THR
B
94
10.354
30.513
−16.315
1.00
35.20
C
ATOM
1029
C
THR
B
94
11.727
27.047
−17.428
1.00
34.67
C
ATOM
1030
O
THR
B
94
11.199
25.961
−17.197
1.00
33.47
O
ATOM
1031
N
ILE
B
95
13.051
27.175
−17.583
1.00
35.62
N
ATOM
1032
CA
ILE
B
95
13.960
26.054
−17.369
1.00
36.37
C
ATOM
1033
CB
ILE
B
95
15.499
26.465
−17.487
1.00
36.16
C
ATOM
1034
CG1
ILE
B
95
15.815
26.979
−18.895
1.00
39.79
C
ATOM
1035
CD1
ILE
B
95
17.240
27.642
−19.070
1.00
39.32
C
ATOM
1036
CG2
ILE
B
95
16.343
25.262
−17.243
1.00
36.87
C
ATOM
1037
C
ILE
B
95
13.739
25.427
−15.998
1.00
35.94
C
ATOM
1038
O
ILE
B
95
13.831
24.194
−15.836
1.00
36.49
O
ATOM
1039
N
GLU
B
96
13.509
26.257
−14.993
1.00
36.30
N
ATOM
1040
CA
GLU
B
96
13.309
25.726
−13.628
1.00
37.91
C
ATOM
1041
CB
GLU
B
96
13.372
26.878
−12.596
1.00
38.48
C
ATOM
1042
CG
GLU
B
96
13.421
26.440
−11.134
1.00
41.71
C
ATOM
1043
CD
GLU
B
96
12.042
26.159
−10.555
1.00
45.38
C
ATOM
1044
OE1
GLU
B
96
11.042
26.752
−11.042
1.00
47.09
O
ATOM
1045
OE2
GLU
B
96
11.967
25.354
−9.600
1.00
46.98
O
ATOM
1046
C
GLU
B
96
11.995
24.913
−13.517
1.00
36.88
C
ATOM
1047
O
GLU
B
96
11.977
23.805
−12.997
1.00
36.45
O
ATOM
1048
N
GLU
B
97
10.909
25.477
−14.028
1.00
36.87
N
ATOM
1049
CA
GLU
B
97
9.602
24.789
−14.010
1.00
36.88
C
ATOM
1050
CB
GLU
B
97
8.552
25.667
−14.663
1.00
36.11
C
ATOM
1051
CG
GLU
B
97
8.177
26.883
−13.781
1.00
38.37
C
ATOM
1052
CD
GLU
B
97
7.264
27.884
−14.452
1.00
38.94
C
ATOM
1053
OE1
GLU
B
97
7.424
28.160
−15.681
1.00
38.42
O
ATOM
1054
OE2
GLU
B
97
6.399
28.435
−13.725
1.00
41.47
O
ATOM
1055
C
GLU
B
97
9.662
23.414
−14.664
1.00
36.23
C
ATOM
1056
O
GLU
B
97
9.071
22.443
−14.171
1.00
36.44
O
ATOM
1057
N
LEU
B
98
10.409
23.313
−15.760
1.00
35.44
N
ATOM
1058
CA
LEU
B
98
10.447
22.090
−16.543
1.00
36.09
C
ATOM
1059
CB
LEU
B
98
10.992
22.400
−17.941
1.00
37.24
C
ATOM
1060
CG
LEU
B
98
10.961
21.395
−19.103
1.00
41.62
C
ATOM
1061
CD1
LEU
B
98
9.587
21.306
−19.833
1.00
41.32
C
ATOM
1062
CD2
LEU
B
98
12.004
21.864
−20.095
1.00
45.35
C
ATOM
1063
C
LEU
B
98
11.290
21.025
−15.870
1.00
36.56
C
ATOM
1064
O
LEU
B
98
11.003
19.822
−15.985
1.00
35.75
O
ATOM
1065
N
SER
B
99
12.322
21.470
−15.156
1.00
37.20
N
ATOM
1066
CA
SER
B
99
13.294
20.563
−14.547
1.00
38.65
C
ATOM
1067
CB
SER
B
99
14.666
21.226
−14.525
1.00
39.66
C
ATOM
1068
OG
SER
B
99
14.626
22.393
−13.710
1.00
45.01
O
ATOM
1069
C
SER
B
99
12.934
20.161
−13.136
1.00
37.67
C
ATOM
1070
O
SER
B
99
13.387
19.139
−12.682
1.00
37.38
O
ATOM
1071
N
ARG
B
100
12.101
20.962
−12.457
1.00
38.83
N
ATOM
1072
CA
ARG
B
100
11.673
20.677
−11.071
1.00
38.07
C
ATOM
1073
CB
ARG
B
100
10.594
21.675
−10.658
1.00
39.03
C
ATOM
1074
CG
ARG
B
100
10.454
21.834
−9.166
1.00
40.88
C
ATOM
1075
CD
ARG
B
100
9.310
22.774
−8.836
1.00
40.98
C
ATOM
1076
NE
ARG
B
100
9.423
24.092
−9.464
1.00
39.64
N
ATOM
1077
CZ
ARG
B
100
8.392
24.898
−9.644
1.00
40.56
C
ATOM
1078
NH1
ARG
B
100
7.189
24.515
−9.231
1.00
44.30
N
ATOM
1079
NH2
ARG
B
100
8.550
26.090
−10.198
1.00
42.36
N
ATOM
1080
C
ARG
B
100
11.121
19.261
−10.945
1.00
37.43
C
ATOM
1081
O
ARG
B
100
10.438
18.783
−11.846
1.00
36.57
O
ATOM
1082
N
ASP
B
101
11.453
18.564
−9.860
1.00
35.80
N
ATOM
1083
CA
ASP
B
101
10.742
17.342
−9.523
1.00
35.10
C
ATOM
1084
CB
ASP
B
101
11.651
16.271
−8.899
1.00
35.75
C
ATOM
1085
CG
ASP
B
101
12.806
15.834
−9.812
1.00
37.07
C
ATOM
1086
OD1
ASP
B
101
12.570
15.518
−11.012
1.00
35.64
O
ATOM
1087
OD2
ASP
B
101
13.952
15.733
−9.275
1.00
38.34
O
ATOM
1088
C
ASP
B
101
9.690
17.753
−8.500
1.00
34.47
C
ATOM
1089
O
ASP
B
101
9.912
18.665
−7.681
1.00
35.01
O
ATOM
1090
N
TRP
B
102
8.540
17.093
−8.525
1.00
33.32
N
ATOM
1091
CA
TRP
B
102
7.468
17.502
−7.641
1.00
31.72
C
ATOM
1092
CB
TRP
B
102
6.491
18.411
−8.419
1.00
32.70
C
ATOM
1093
CG
TRP
B
102
5.866
17.687
−9.554
1.00
30.91
C
ATOM
1094
CD1
TRP
B
102
6.433
17.389
−10.754
1.00
31.44
C
ATOM
1095
NE1
TRP
B
102
5.544
16.652
−11.540
1.00
33.38
N
ATOM
1096
CE2
TRP
B
102
4.386
16.454
−10.833
1.00
34.03
C
ATOM
1097
CD2
TRP
B
102
4.562
17.079
−9.552
1.00
34.03
C
ATOM
1098
CE3
TRP
B
102
3.512
17.033
−8.620
1.00
33.01
C
ATOM
1099
CZ3
TRP
B
102
2.309
16.373
−8.993
1.00
30.04
C
ATOM
1100
CH2
TRP
B
102
2.188
15.734
−10.255
1.00
31.03
C
ATOM
1101
CZ2
TRP
B
102
3.206
15.764
−11.184
1.00
31.94
C
ATOM
1102
C
TRP
B
102
6.829
16.320
−6.880
1.00
31.64
C
ATOM
1103
O
TRP
B
102
7.038
15.140
−7.209
1.00
31.20
O
ATOM
1104
N
PHE
B
103
6.114
16.653
−5.800
1.00
30.85
N
ATOM
1105
CA
PHE
B
103
5.628
15.684
−4.827
1.00
29.60
C
ATOM
1106
CB
PHE
B
103
6.029
16.180
−3.425
1.00
30.18
C
ATOM
1107
CG
PHE
B
103
5.321
15.507
−2.268
1.00
31.54
C
ATOM
1108
CD1
PHE
B
103
5.742
14.284
−1.798
1.00
31.56
C
ATOM
1109
CE1
PHE
B
103
5.122
13.681
−0.692
1.00
30.41
C
ATOM
1110
CZ
PHE
B
103
4.055
14.329
−0.046
1.00
31.78
C
ATOM
1111
CE2
PHE
B
103
3.635
15.599
−0.483
1.00
30.83
C
ATOM
1112
CD2
PHE
B
103
4.273
16.174
−1.597
1.00
33.14
C
ATOM
1113
C
PHE
B
103
4.118
15.612
−4.935
1.00
27.88
C
ATOM
1114
O
PHE
B
103
3.473
16.646
−5.063
1.00
28.45
O
ATOM
1115
N
MET
B
104
3.598
14.391
−4.875
1.00
27.19
N
ATOM
1116
CA
MET
B
104
2.163
14.120
−4.772
1.00
27.44
C
ATOM
1117
CB
MET
B
104
1.715
13.163
−5.899
1.00
26.04
C
ATOM
1118
CG
MET
B
104
1.798
13.758
−7.355
1.00
28.37
C
ATOM
1119
SD
MET
B
104
1.632
12.389
−8.528
1.00
26.62
S
ATOM
1120
CE
MET
B
104
3.295
11.830
−8.571
1.00
26.34
C
ATOM
1121
C
MET
B
104
1.913
13.456
−3.389
1.00
27.60
C
ATOM
1122
O
MET
B
104
2.502
12.434
−3.068
1.00
26.49
O
ATOM
1123
N
LEU
B
105
1.056
14.072
−2.583
1.00
26.42
N
ATOM
1124
CA
LEU
B
105
0.616
13.447
−1.317
1.00
26.58
C
ATOM
1125
CB
LEU
B
105
−0.240
14.454
−0.508
1.00
25.53
C
ATOM
1126
CG
LEU
B
105
−0.660
14.024
0.917
1.00
28.52
C
ATOM
1127
CD1
LEU
B
105
0.620
13.782
1.774
1.00
26.80
C
ATOM
1128
CD2
LEU
B
105
−1.509
15.149
1.416
1.00
28.79
C
ATOM
1129
C
LEU
B
105
−0.185
12.189
−1.571
1.00
26.02
C
ATOM
1130
O
LEU
B
105
−0.030
11.227
−0.858
1.00
26.32
O
ATOM
1131
N
MET
B
106
−1.086
12.213
−2.572
1.00
26.57
N
ATOM
1132
CA
MET
B
106
−1.909
11.043
−2.919
1.00
25.33
C
ATOM
1133
CB
MET
B
106
−3.414
11.381
−2.722
1.00
24.16
C
ATOM
1134
CG
MET
B
106
−3.718
11.818
−1.267
1.00
27.74
C
ATOM
1135
SD
MET
B
106
−5.495
12.138
−1.007
1.00
25.66
S
ATOM
1136
CE
MET
B
106
−5.818
10.701
0.032
1.00
35.03
C
ATOM
1137
C
MET
B
106
−1.641
10.741
−4.397
1.00
26.10
C
ATOM
1138
O
MET
B
106
−2.439
11.106
−5.263
1.00
24.95
O
ATOM
1139
N
PRO
B
107
−0.515
10.079
−4.684
1.00
27.23
N
ATOM
1140
CA
PRO
B
107
−0.083
9.969
−6.107
1.00
26.85
C
ATOM
1141
CB
PRO
B
107
1.220
9.184
−6.024
1.00
26.93
C
ATOM
1142
CG
PRO
B
107
1.622
9.205
−4.482
1.00
26.97
C
ATOM
1143
CD
PRO
B
107
0.333
9.284
−3.763
1.00
26.75
C
ATOM
1144
C
PRO
B
107
−1.085
9.168
−6.958
1.00
26.73
C
ATOM
1145
O
PRO
B
107
−1.699
8.178
−6.490
1.00
26.39
O
ATOM
1146
N
LYS
B
108
−1.238
9.625
−8.202
1.00
27.58
N
ATOM
1147
CA
LYS
B
108
−2.047
8.964
−9.208
1.00
28.66
C
ATOM
1148
CB
LYS
B
108
−3.361
9.741
−9.422
1.00
28.49
C
ATOM
1149
CG
LYS
B
108
−4.375
9.513
−8.277
1.00
28.11
C
ATOM
1150
CD
LYS
B
108
−4.773
8.044
−8.260
1.00
30.78
C
ATOM
1151
CE
LYS
B
108
−5.300
7.575
−6.971
1.00
32.01
C
ATOM
1152
NZ
LYS
B
108
−4.282
7.664
−5.906
1.00
33.62
N
ATOM
1153
C
LYS
B
108
−1.212
9.009
−10.485
1.00
28.71
C
ATOM
1154
O
LYS
B
108
−0.620
10.034
−10.802
1.00
28.16
O
ATOM
1155
N
GLN
B
109
−1.132
7.879
−11.171
1.00
30.52
N
ATOM
1156
CA
GLN
B
109
−0.373
7.809
−12.435
1.00
33.68
C
ATOM
1157
CB
GLN
B
109
1.078
7.372
−12.187
1.00
34.23
C
ATOM
1158
CG
GLN
B
109
1.943
7.302
−13.432
1.00
39.99
C
ATOM
1159
CD
GLN
B
109
3.272
6.642
−13.153
1.00
47.20
C
ATOM
1160
OE1
GLN
B
109
4.126
7.218
−12.489
1.00
52.68
O
ATOM
1161
NE2
GLN
B
109
3.448
5.416
−13.636
1.00
51.24
N
ATOM
1162
C
GLN
B
109
−1.066
6.845
−13.352
1.00
34.01
C
ATOM
1163
O
GLN
B
109
−1.408
5.722
−12.931
1.00
34.27
O
ATOM
1164
N
LYS
B
110
−1.283
7.290
−14.595
1.00
34.52
N
ATOM
1165
CA
LYS
B
110
−1.941
6.463
−15.617
1.00
35.64
C
ATOM
1166
CB
LYS
B
110
−3.318
7.045
−15.923
1.00
35.09
C
ATOM
1167
CG
LYS
B
110
−4.199
6.200
−16.799
1.00
36.36
C
ATOM
1168
CD
LYS
B
110
−5.256
7.078
−17.360
1.00
37.52
C
ATOM
1169
CE
LYS
B
110
−6.197
6.331
−18.301
1.00
43.96
C
ATOM
1170
NZ
LYS
B
110
−6.738
5.149
−17.583
1.00
45.73
N
ATOM
1171
C
LYS
B
110
−1.073
6.512
−16.889
1.00
35.81
C
ATOM
1172
O
LYS
B
110
−0.677
7.581
−17.306
1.00
34.99
O
ATOM
1173
N
VAL
B
111
−0.765
5.344
−17.453
1.00
36.14
N
ATOM
1174
CA
VAL
B
111
−0.183
5.256
−18.790
1.00
37.37
C
ATOM
1175
CB
VAL
B
111
0.595
3.969
−18.988
1.00
38.40
C
ATOM
1176
CG1
VAL
B
111
1.096
3.874
−20.451
1.00
40.21
C
ATOM
1177
CG2
VAL
B
111
1.746
3.934
−18.025
1.00
39.38
C
ATOM
1178
C
VAL
B
111
−1.329
5.314
−19.766
1.00
37.36
C
ATOM
1179
O
VAL
B
111
−2.230
4.493
−19.737
1.00
37.69
O
ATOM
1180
N
GLU
B
112
−1.367
6.331
−20.596
1.00
36.83
N
ATOM
1181
CA
GLU
B
112
−2.436
6.329
−21.550
1.00
37.26
C
ATOM
1182
CB
GLU
B
112
−3.334
7.501
−21.290
1.00
37.53
C
ATOM
1183
CG
GLU
B
112
−4.730
7.186
−21.687
1.00
42.45
C
ATOM
1184
CD
GLU
B
112
−5.518
8.434
−21.769
1.00
47.91
C
ATOM
1185
OE1
GLU
B
112
−6.665
8.423
−21.268
1.00
49.77
O
ATOM
1186
OE2
GLU
B
112
−4.951
9.421
−22.317
1.00
47.40
O
ATOM
1187
C
GLU
B
112
−1.915
6.361
−22.986
1.00
36.04
C
ATOM
1188
O
GLU
B
112
−1.497
7.415
−23.484
1.00
34.78
O
ATOM
1189
N
GLY
B
113
−1.920
5.204
−23.644
1.00
35.37
N
ATOM
1190
CA
GLY
B
113
−1.239
5.135
−24.935
1.00
33.99
C
ATOM
1191
C
GLY
B
113
0.262
5.420
−24.706
1.00
32.46
C
ATOM
1192
O
GLY
B
113
0.895
4.810
−23.819
1.00
33.59
O
ATOM
1193
N
PRO
B
114
0.842
6.341
−25.484
1.00
30.86
N
ATOM
1194
CA
PRO
B
114
2.254
6.728
−25.432
1.00
30.15
C
ATOM
1195
CB
PRO
B
114
2.491
7.285
−26.845
1.00
30.38
C
ATOM
1196
CG
PRO
B
114
1.188
7.915
−27.171
1.00
30.21
C
ATOM
1197
CD
PRO
B
114
0.128
7.066
−26.553
1.00
31.78
C
ATOM
1198
C
PRO
B
114
2.584
7.817
−24.386
1.00
28.89
C
ATOM
1199
O
PRO
B
114
3.733
8.284
−24.323
1.00
27.26
O
ATOM
1200
N
LEU
B
115
1.603
8.178
−23.538
1.00
27.32
N
ATOM
1201
CA
LEU
B
115
1.751
9.275
−22.578
1.00
27.63
C
ATOM
1202
CB
LEU
B
115
0.833
10.464
−22.938
1.00
26.73
C
ATOM
1203
CG
LEU
B
115
0.951
11.005
−24.372
1.00
28.81
C
ATOM
1204
CD1
LEU
B
115
−0.120
12.044
−24.555
1.00
28.14
C
ATOM
1205
CD2
LEU
B
115
2.323
11.667
−24.558
1.00
27.61
C
ATOM
1206
C
LEU
B
115
1.456
8.803
−21.149
1.00
27.69
C
ATOM
1207
O
LEU
B
115
0.695
7.849
−20.937
1.00
28.97
O
ATOM
1208
N
CYS
B
116
2.077
9.493
−20.204
1.00
28.03
N
ATOM
1209
CA
CYS
B
116
1.923
9.240
−18.787
1.00
27.99
C
ATOM
1210
CB
CYS
B
116
3.288
8.988
−18.165
1.00
28.84
C
ATOM
1211
SG
CYS
B
116
3.202
8.685
−16.342
1.00
32.13
S
ATOM
1212
C
CYS
B
116
1.275
10.452
−18.147
1.00
28.28
C
ATOM
1213
O
CYS
B
116
1.700
11.596
−18.392
1.00
27.83
O
ATOM
1214
N
ILE
B
117
0.204
10.204
−17.354
1.00
27.49
N
ATOM
1215
CA
ILE
B
117
−0.572
11.279
−16.710
1.00
26.02
C
ATOM
1216
CB
ILE
B
117
−2.093
11.221
−17.073
1.00
26.73
C
ATOM
1217
CG1
ILE
B
117
−2.262
11.134
−18.605
1.00
27.69
C
ATOM
1218
CD1
ILE
B
117
−3.458
10.398
−19.049
1.00
28.54
C
ATOM
1219
CG2
ILE
B
117
−2.878
12.453
−16.465
1.00
25.95
C
ATOM
1220
C
ILE
B
117
−0.391
11.052
−15.192
1.00
24.22
C
ATOM
1221
O
ILE
B
117
−0.574
9.957
−14.719
1.00
26.21
O
ATOM
1222
N
ARG
B
118
0.002
12.093
−14.495
1.00
24.83
N
ATOM
1223
CA
ARG
B
118
0.151
12.069
−13.050
1.00
24.60
C
ATOM
1224
CB
ARG
B
118
1.625
12.324
−12.676
1.00
26.12
C
ATOM
1225
CG
ARG
B
118
2.554
11.240
−13.053
1.00
29.98
C
ATOM
1226
CD
ARG
B
118
3.976
11.644
−12.680
1.00
36.27
C
ATOM
1227
NE
ARG
B
118
4.833
10.487
−12.835
1.00
43.72
N
ATOM
1228
CZ
ARG
B
118
5.739
10.363
−13.792
1.00
48.66
C
ATOM
1229
NH1
ARG
B
118
5.935
11.371
−14.654
1.00
50.62
N
ATOM
1230
NH2
ARG
B
118
6.456
9.235
−13.879
1.00
50.32
N
ATOM
1231
C
ARG
B
118
−0.648
13.195
−12.465
1.00
23.69
C
ATOM
1232
O
ARG
B
118
−0.738
14.276
−13.030
1.00
22.96
O
ATOM
1233
N
ILE
B
119
−1.170
12.992
−11.254
1.00
24.51
N
ATOM
1234
CA
ILE
B
119
−1.918
14.071
−10.630
1.00
23.38
C
ATOM
1235
CB
ILE
B
119
−3.379
14.189
−11.220
1.00
25.08
C
ATOM
1236
CG1
ILE
B
119
−4.168
15.391
−10.625
1.00
24.01
C
ATOM
1237
CD1
ILE
B
119
−5.698
15.456
−11.077
1.00
24.74
C
ATOM
1238
CG2
ILE
B
119
−4.097
12.864
−11.167
1.00
26.19
C
ATOM
1239
C
ILE
B
119
−1.927
13.744
−9.149
1.00
22.60
C
ATOM
1240
O
ILE
B
119
−1.861
12.601
−8.768
1.00
23.10
O
ATOM
1241
N
ASP
B
120
−1.893
14.786
−8.349
1.00
22.84
N
ATOM
1242
CA
ASP
B
120
−2.059
14.611
−6.892
1.00
24.58
C
ATOM
1243
CB
ASP
B
120
−1.358
15.710
−6.147
1.00
23.29
C
ATOM
1244
CG
ASP
B
120
−1.252
15.431
−4.633
1.00
25.72
C
ATOM
1245
OD1
ASP
B
120
−1.856
14.473
−4.136
1.00
26.52
O
ATOM
1246
OD2
ASP
B
120
−0.495
16.173
−3.961
1.00
27.39
O
ATOM
1247
C
ASP
B
120
−3.561
14.713
−6.580
1.00
22.94
C
ATOM
1248
O
ASP
B
120
−4.145
15.773
−6.725
1.00
23.18
O
ATOM
1249
N
GLN
B
121
−4.127
13.597
−6.196
1.00
23.75
N
ATOM
1250
CA
GLN
B
121
−5.534
13.493
−5.718
1.00
24.41
C
ATOM
1251
CB
GLN
B
121
−5.888
12.008
−5.498
1.00
23.59
C
ATOM
1252
CG
GLN
B
121
−7.357
11.742
−4.999
1.00
24.61
C
ATOM
1253
CD
GLN
B
121
−7.689
10.313
−4.820
1.00
25.20
C
ATOM
1254
OE1
GLN
B
121
−6.826
9.468
−4.792
1.00
24.43
O
ATOM
1255
NE2
GLN
B
121
−8.996
10.017
−4.688
1.00
28.25
N
ATOM
1256
C
GLN
B
121
−5.863
14.386
−4.487
1.00
24.49
C
ATOM
1257
O
GLN
B
121
−7.026
14.736
−4.267
1.00
24.40
O
ATOM
1258
N
ALA
B
122
−4.842
14.834
−3.740
1.00
25.85
N
ATOM
1259
CA
ALA
B
122
−5.058
15.623
−2.509
1.00
24.80
C
ATOM
1260
CB
ALA
B
122
−3.813
15.587
−1.658
1.00
25.27
C
ATOM
1261
C
ALA
B
122
−5.372
17.049
−2.846
1.00
25.48
C
ATOM
1262
O
ALA
B
122
−5.871
17.837
−2.014
1.00
23.88
O
ATOM
1263
N
ILE
B
123
−5.033
17.457
−4.065
1.00
25.50
N
ATOM
1264
CA
ILE
B
123
−5.136
18.876
−4.370
1.00
26.71
C
ATOM
1265
CB
ILE
B
123
−4.088
19.273
−5.469
1.00
27.03
C
ATOM
1266
CG1
ILE
B
123
−2.664
19.148
−4.895
1.00
28.82
C
ATOM
1267
CD1
ILE
B
123
−2.252
20.255
−3.962
1.00
28.25
C
ATOM
1268
CG2
ILE
B
123
−4.368
20.704
−6.006
1.00
29.25
C
ATOM
1269
C
ILE
B
123
−6.541
19.345
−4.791
1.00
28.30
C
ATOM
1270
O
ILE
B
123
−7.114
18.843
−5.810
1.00
28.00
O
ATOM
1271
N
MET
B
124
−7.059
20.359
−4.072
1.00
27.99
N
ATOM
1272
CA
MET
B
124
−8.433
20.849
−4.267
1.00
30.20
C
ATOM
1273
CB
MET
B
124
−9.407
20.226
−3.257
1.00
28.85
C
ATOM
1274
CG
MET
B
124
−9.245
18.768
−3.159
1.00
30.84
C
ATOM
1275
SD
MET
B
124
−10.621
18.153
−2.165
1.00
33.91
S
ATOM
1276
CE
MET
B
124
−10.006
16.631
−1.750
1.00
24.31
C
ATOM
1277
C
MET
B
124
−8.505
22.326
−4.146
1.00
31.04
C
ATOM
1278
O
MET
B
124
−7.600
22.948
−3.608
1.00
31.15
O
ATOM
1279
N
ASP
B
125
−9.577
22.892
−4.694
1.00
33.33
N
ATOM
1280
CA
ASP
B
125
−9.940
24.291
−4.503
1.00
34.92
C
ATOM
1281
CB
ASP
B
125
−10.269
24.509
−3.012
1.00
36.08
C
ATOM
1282
CG
ASP
B
125
−11.451
23.718
−2.579
1.00
38.58
C
ATOM
1283
OD1
ASP
B
125
−12.498
23.851
−3.285
1.00
46.09
O
ATOM
1284
OD2
ASP
B
125
−11.342
22.965
−1.572
1.00
41.80
O
ATOM
1285
C
ASP
B
125
−8.930
25.325
−4.949
1.00
35.72
C
ATOM
1286
O
ASP
B
125
−8.958
26.442
−4.455
1.00
36.05
O
ATOM
1287
N
LYS
B
126
−8.045
24.987
−5.880
1.00
34.36
N
ATOM
1288
CA
LYS
B
126
−7.079
25.938
−6.355
1.00
34.46
C
ATOM
1289
CB
LYS
B
126
−5.654
25.347
−6.229
1.00
35.61
C
ATOM
1290
CG
LYS
B
126
−5.123
25.518
−4.749
1.00
35.45
C
ATOM
1291
CD
LYS
B
126
−4.231
24.371
−4.247
1.00
41.21
C
ATOM
1292
CE
LYS
B
126
−4.235
24.232
−2.709
1.00
40.11
C
ATOM
1293
NZ
LYS
B
126
−5.023
23.010
−2.047
1.00
39.60
N
ATOM
1294
C
LYS
B
126
−7.410
26.445
−7.763
1.00
35.16
C
ATOM
1295
O
LYS
B
126
−8.172
25.801
−8.495
1.00
34.91
O
ATOM
1296
N
ASN
B
127
−6.917
27.635
−8.091
1.00
34.53
N
ATOM
1297
CA
ASN
B
127
−6.852
28.104
−9.463
1.00
35.83
C
ATOM
1298
CB
ASN
B
127
−6.784
29.634
−9.482
1.00
36.09
C
ATOM
1299
CG
ASN
B
127
−8.059
30.259
−8.963
1.00
39.59
C
ATOM
1300
OD1
ASN
B
127
−9.151
29.895
−9.403
1.00
42.15
O
ATOM
1301
ND2
ASN
B
127
−7.935
31.181
−8.010
1.00
41.71
N
ATOM
1302
C
ASN
B
127
−5.608
27.460
−10.123
1.00
35.83
C
ATOM
1303
O
ASN
B
127
−4.471
27.660
−9.646
1.00
35.54
O
ATOM
1304
N
ILE
B
128
−5.838
26.643
−11.153
1.00
34.49
N
ATOM
1305
CA
ILE
B
128
−4.762
25.838
−11.739
1.00
34.62
C
ATOM
1306
CB
ILE
B
128
−5.119
24.306
−11.680
1.00
34.79
C
ATOM
1307
CG1
ILE
B
128
−5.265
23.784
−10.233
1.00
32.44
C
ATOM
1308
CD1
ILE
B
128
−3.957
23.744
−9.465
1.00
36.65
C
ATOM
1309
CG2
ILE
B
128
−4.116
23.458
−12.496
1.00
33.81
C
ATOM
1310
C
ILE
B
128
−4.571
26.280
−13.192
1.00
34.82
C
ATOM
1311
O
ILE
B
128
−5.550
26.529
−13.892
1.00
35.00
O
ATOM
1312
N
MET
B
129
−3.314
26.404
−13.643
1.00
35.61
N
ATOM
1313
CA
MET
B
129
−2.996
26.814
−15.021
1.00
34.86
C
ATOM
1314
CB
MET
B
129
−2.261
28.179
−15.048
1.00
35.13
C
ATOM
1315
CG
MET
B
129
−1.751
28.640
−16.447
1.00
35.56
C
ATOM
1316
SD
MET
B
129
−3.035
29.030
−17.670
1.00
38.68
S
ATOM
1317
CE
MET
B
129
−3.538
30.686
−17.157
1.00
41.92
C
ATOM
1318
C
MET
B
129
−2.130
25.742
−15.712
1.00
34.42
C
ATOM
1319
O
MET
B
129
−1.032
25.415
−15.221
1.00
33.25
O
ATOM
1320
N
LEU
B
130
−2.612
25.201
−16.832
1.00
33.00
N
ATOM
1321
CA
LEU
B
130
−1.798
24.222
−17.574
1.00
32.79
C
ATOM
1322
CB
LEU
B
130
−2.667
23.270
−18.395
1.00
33.33
C
ATOM
1323
CG
LEU
B
130
−3.805
22.507
−17.746
1.00
34.39
C
ATOM
1324
CD1
LEU
B
130
−4.218
21.298
−18.640
1.00
35.78
C
ATOM
1325
CD2
LEU
B
130
−3.454
22.026
−16.355
1.00
33.03
C
ATOM
1326
C
LEU
B
130
−0.867
25.000
−18.501
1.00
31.81
C
ATOM
1327
O
LEU
B
130
−1.316
25.839
−19.251
1.00
31.56
O
ATOM
1328
N
LYS
B
131
0.425
24.706
−18.407
1.00
31.06
N
ATOM
1329
CA
LYS
B
131
1.487
25.276
−19.233
1.00
30.62
C
ATOM
1330
CB
LYS
B
131
2.465
26.072
−18.367
1.00
31.05
C
ATOM
1331
CG
LYS
B
131
1.907
27.398
−17.944
1.00
33.09
C
ATOM
1332
CD
LYS
B
131
2.876
28.133
−17.055
1.00
35.17
C
ATOM
1333
CE
LYS
B
131
2.199
29.374
−16.485
1.00
38.38
C
ATOM
1334
NZ
LYS
B
131
3.249
30.258
−15.877
1.00
39.16
N
ATOM
1335
C
LYS
B
131
2.215
24.125
−19.926
1.00
29.36
C
ATOM
1336
O
LYS
B
131
2.375
23.043
−19.365
1.00
29.14
O
ATOM
1337
N
ALA
B
132
2.596
24.318
−21.183
1.00
27.61
N
ATOM
1338
CA
ALA
B
132
3.286
23.232
−21.881
1.00
26.94
C
ATOM
1339
CB
ALA
B
132
2.302
22.385
−22.757
1.00
24.90
C
ATOM
1340
C
ALA
B
132
4.443
23.733
−22.737
1.00
26.64
C
ATOM
1341
O
ALA
B
132
4.454
24.875
−23.193
1.00
26.99
O
ATOM
1342
N
ASN
B
133
5.405
22.846
−22.933
1.00
27.01
N
ATOM
1343
CA
ASN
B
133
6.506
23.033
−23.898
1.00
27.23
C
ATOM
1344
CB
ASN
B
133
7.863
22.830
−23.177
1.00
28.41
C
ATOM
1345
CG
ASN
B
133
8.211
24.006
−22.255
1.00
30.04
C
ATOM
1346
OD1
ASN
B
133
7.344
24.721
−21.806
1.00
31.04
O
ATOM
1347
ND2
ASN
B
133
9.489
24.210
−21.993
1.00
34.78
N
ATOM
1348
C
ASN
B
133
6.293
22.000
−25.026
1.00
27.01
C
ATOM
1349
O
ASN
B
133
6.084
20.793
−24.784
1.00
25.65
O
ATOM
1350
N
PHE
B
134
6.295
22.469
−26.277
1.00
28.15
N
ATOM
1351
CA
PHE
B
134
5.929
21.577
−27.349
1.00
29.30
C
ATOM
1352
CB
PHE
B
134
4.400
21.283
−27.328
1.00
30.21
C
ATOM
1353
CG
PHE
B
134
3.533
22.520
−27.414
1.00
32.57
C
ATOM
1354
CD1
PHE
B
134
3.094
23.009
−28.647
1.00
33.22
C
ATOM
1355
CE1
PHE
B
134
2.312
24.154
−28.704
1.00
32.79
C
ATOM
1356
CZ
PHE
B
134
1.955
24.809
−27.541
1.00
33.90
C
ATOM
1357
CE2
PHE
B
134
2.401
24.324
−26.305
1.00
32.40
C
ATOM
1358
CD2
PHE
B
134
3.165
23.197
−26.257
1.00
31.50
C
ATOM
1359
C
PHE
B
134
6.329
22.201
−28.682
1.00
29.84
C
ATOM
1360
O
PHE
B
134
6.534
23.409
−28.792
1.00
30.16
O
ATOM
1361
N
SER
B
135
6.419
21.375
−29.710
1.00
31.15
N
ATOM
1362
CA
SER
B
135
6.679
21.941
−31.053
1.00
32.23
C
ATOM
1363
CB
SER
B
135
7.628
21.052
−31.812
1.00
32.51
C
ATOM
1364
OG
SER
B
135
7.036
19.812
−32.002
1.00
33.57
O
ATOM
1365
C
SER
B
135
5.386
22.073
−31.827
1.00
33.12
C
ATOM
1366
O
SER
B
135
4.420
21.371
−31.537
1.00
31.51
O
ATOM
1367
N
VAL
B
136
5.389
22.959
−32.839
1.00
34.96
N
ATOM
1368
CA
VAL
B
136
4.225
23.143
−33.685
1.00
36.92
C
ATOM
1369
CB
VAL
B
136
3.385
24.440
−33.371
1.00
37.96
C
ATOM
1370
CG1
VAL
B
136
2.815
24.423
−31.922
1.00
37.33
C
ATOM
1371
CG2
VAL
B
136
4.185
25.652
−33.544
1.00
38.33
C
ATOM
1372
C
VAL
B
136
4.701
23.143
−35.116
1.00
38.73
C
ATOM
1373
O
VAL
B
136
5.834
23.563
−35.409
1.00
38.26
O
ATOM
1374
N
ILE
B
137
3.882
22.554
−35.969
1.00
40.79
N
ATOM
1375
CA
ILE
B
137
4.031
22.698
−37.411
1.00
44.55
C
ATOM
1376
CB
ILE
B
137
4.633
21.429
−38.099
1.00
44.67
C
ATOM
1377
CG1
ILE
B
137
3.919
20.174
−37.651
1.00
45.11
C
ATOM
1378
CD1
ILE
B
137
4.421
18.930
−38.328
1.00
49.18
C
ATOM
1379
CG2
ILE
B
137
6.109
21.293
−37.822
1.00
47.14
C
ATOM
1380
C
ILE
B
137
2.633
22.973
−37.940
1.00
45.83
C
ATOM
1381
O
ILE
B
137
1.658
22.408
−37.420
1.00
46.23
O
ATOM
1382
N
PHE
B
138
2.539
23.867
−38.932
1.00
48.16
N
ATOM
1383
CA
PHE
B
138
1.279
24.178
−39.629
1.00
50.06
C
ATOM
1384
CB
PHE
B
138
0.792
22.974
−40.474
1.00
51.11
C
ATOM
1385
CG
PHE
B
138
1.852
22.411
−41.398
1.00
53.72
C
ATOM
1386
CD1
PHE
B
138
2.183
21.054
−41.358
1.00
57.35
C
ATOM
1387
CE1
PHE
B
138
3.189
20.518
−42.204
1.00
57.68
C
ATOM
1388
CZ
PHE
B
138
3.865
21.353
−43.080
1.00
55.86
C
ATOM
1389
CE2
PHE
B
138
3.545
22.720
−43.124
1.00
57.45
C
ATOM
1390
CD2
PHE
B
138
2.543
23.242
−42.286
1.00
55.69
C
ATOM
1391
C
PHE
B
138
0.210
24.607
−38.630
1.00
50.34
C
ATOM
1392
O
PHE
B
138
−0.923
24.093
−38.663
1.00
50.82
O
ATOM
1393
N
ASP
B
139
0.598
25.525
−37.741
1.00
50.41
N
ATOM
1394
CA
ASP
B
139
−0.252
26.037
−36.637
1.00
50.56
C
ATOM
1395
CB
ASP
B
139
−1.150
27.178
−37.125
1.00
52.14
C
ATOM
1396
CG
ASP
B
139
−0.371
28.481
−37.289
1.00
54.55
C
ATOM
1397
OD1
ASP
B
139
0.301
28.897
−36.307
1.00
57.23
O
ATOM
1398
OD2
ASP
B
139
−0.409
29.066
−38.398
0.50
56.46
O
ATOM
1399
C
ASP
B
139
−1.004
25.031
−35.770
1.00
49.51
C
ATOM
1400
O
ASP
B
139
−2.110
25.289
−35.243
1.00
49.37
O
ATOM
1401
N
ARG
B
140
−0.355
23.891
−35.580
1.00
47.68
N
ATOM
1402
CA
ARG
B
140
−0.920
22.771
−34.875
1.00
46.64
C
ATOM
1403
CB
ARG
B
140
−1.361
21.736
−35.917
1.00
47.18
C
ATOM
1404
CG
ARG
B
140
−1.906
20.430
−35.365
1.00
50.69
C
ATOM
1405
CD
ARG
B
140
−1.832
19.264
−36.415
1.00
52.62
C
ATOM
1406
NE
ARG
B
140
−0.462
19.002
−36.903
1.00
62.39
N
ATOM
1407
CZ
ARG
B
140
0.398
18.184
−36.289
1.00
65.34
C
ATOM
1408
NH1
ARG
B
140
0.013
17.558
−35.174
1.00
65.52
N
ATOM
1409
NH2
ARG
B
140
1.629
17.979
−36.783
1.00
64.58
N
ATOM
1410
C
ARG
B
140
0.174
22.207
−33.955
1.00
43.25
C
ATOM
1411
O
ARG
B
140
1.338
22.141
−34.342
1.00
41.78
O
ATOM
1412
N
LEU
B
141
−0.196
21.798
−32.742
1.00
40.18
N
ATOM
1413
CA
LEU
B
141
0.762
21.133
−31.854
1.00
38.38
C
ATOM
1414
CB
LEU
B
141
0.160
20.825
−30.457
1.00
37.77
C
ATOM
1415
CG
LEU
B
141
1.045
20.010
−29.474
1.00
36.52
C
ATOM
1416
CD1
LEU
B
141
0.754
20.416
−28.016
1.00
35.80
C
ATOM
1417
CD2
LEU
B
141
0.821
18.523
−29.680
1.00
30.24
C
ATOM
1418
C
LEU
B
141
1.214
19.859
−32.553
1.00
38.09
C
ATOM
1419
O
LEU
B
141
0.386
19.077
−33.023
1.00
37.31
O
ATOM
1420
N
GLU
B
142
2.535
19.671
−32.607
1.00
37.00
N
ATOM
1421
CA
GLU
B
142
3.161
18.538
−33.253
1.00
36.10
C
ATOM
1422
CB
GLU
B
142
4.385
19.046
−34.050
1.00
36.59
C
ATOM
1423
CG
GLU
B
142
5.078
17.967
−34.887
1.00
38.15
C
ATOM
1424
CD
GLU
B
142
6.464
18.401
−35.444
1.00
40.42
C
ATOM
1425
OE1
GLU
B
142
6.918
17.751
−36.404
1.00
44.80
O
ATOM
1426
OE2
GLU
B
142
7.121
19.345
−34.931
1.00
44.67
O
ATOM
1427
C
GLU
B
142
3.586
17.478
−32.219
1.00
33.59
C
ATOM
1428
O
GLU
B
142
3.102
16.346
−32.228
1.00
32.76
O
ATOM
1429
N
THR
B
143
4.496
17.869
−31.332
1.00
32.21
N
ATOM
1430
CA
THR
B
143
5.113
16.979
−30.334
1.00
30.26
C
ATOM
1431
CB
THR
B
143
6.590
16.671
−30.699
1.00
30.51
C
ATOM
1432
OG1
THR
B
143
6.584
15.914
−31.919
1.00
33.87
O
ATOM
1433
CG2
THR
B
143
7.249
15.807
−29.661
1.00
27.91
C
ATOM
1434
C
THR
B
143
5.091
17.688
−28.988
1.00
28.93
C
ATOM
1435
O
THR
B
143
5.617
18.800
−28.852
1.00
30.12
O
ATOM
1436
N
LEU
B
144
4.487
17.032
−28.002
1.00
27.73
N
ATOM
1437
CA
LEU
B
144
4.567
17.508
−26.616
1.00
26.43
C
ATOM
1438
CB
LEU
B
144
3.431
16.875
−25.801
1.00
26.11
C
ATOM
1439
CG
LEU
B
144
3.403
17.233
−24.313
1.00
24.22
C
ATOM
1440
CD1
LEU
B
144
3.063
18.671
−24.183
1.00
22.62
C
ATOM
1441
CD2
LEU
B
144
2.368
16.369
−23.592
1.00
25.40
C
ATOM
1442
C
LEU
B
144
5.925
17.128
−26.008
1.00
26.12
C
ATOM
1443
O
LEU
B
144
6.324
15.957
−26.032
1.00
26.26
O
ATOM
1444
N
ILE
B
145
6.594
18.101
−25.407
1.00
26.39
N
ATOM
1445
CA
ILE
B
145
7.767
17.789
−24.574
1.00
27.56
C
ATOM
1446
CB
ILE
B
145
8.807
18.976
−24.557
1.00
27.90
C
ATOM
1447
CG1
ILE
B
145
9.241
19.389
−25.990
1.00
31.80
C
ATOM
1448
CD1
ILE
B
145
9.501
18.216
−26.807
1.00
32.94
C
ATOM
1449
CG2
ILE
B
145
10.021
18.674
−23.598
1.00
27.03
C
ATOM
1450
C
ILE
B
145
7.278
17.493
−23.132
1.00
26.46
C
ATOM
1451
O
ILE
B
145
7.527
16.432
−22.576
1.00
25.81
O
ATOM
1452
N
LEU
B
146
6.530
18.428
−22.568
1.00
26.06
N
ATOM
1453
CA
LEU
B
146
6.041
18.267
−21.202
1.00
26.05
C
ATOM
1454
CB
LEU
B
146
7.173
18.571
−20.208
1.00
24.89
C
ATOM
1455
CG
LEU
B
146
6.931
18.388
−18.678
1.00
26.17
C
ATOM
1456
CD1
LEU
B
146
6.582
16.951
−18.314
1.00
25.01
C
ATOM
1457
CD2
LEU
B
146
8.135
18.936
−17.871
1.00
27.73
C
ATOM
1458
C
LEU
B
146
4.890
19.191
−20.970
1.00
24.78
C
ATOM
1459
O
LEU
B
146
4.935
20.345
−21.394
1.00
26.29
O
ATOM
1460
N
LEU
B
147
3.863
18.723
−20.243
1.00
24.66
N
ATOM
1461
CA
LEU
B
147
2.797
19.643
−19.856
1.00
23.39
C
ATOM
1462
CB
LEU
B
147
1.441
19.193
−20.441
1.00
23.05
C
ATOM
1463
CG
LEU
B
147
0.225
20.095
−20.123
1.00
24.92
C
ATOM
1464
CD1
LEU
B
147
−0.772
19.974
−21.269
1.00
24.09
C
ATOM
1465
CD2
LEU
B
147
−0.444
19.655
−18.790
1.00
25.78
C
ATOM
1466
C
LEU
B
147
2.752
19.524
−18.346
1.00
23.23
C
ATOM
1467
O
LEU
B
147
2.810
18.426
−17.860
1.00
23.78
O
ATOM
1468
N
ARG
B
148
2.610
20.634
−17.638
1.00
24.18
N
ATOM
1469
CA
ARG
B
148
2.443
20.592
−16.171
1.00
25.22
C
ATOM
1470
CB
ARG
B
148
3.744
20.991
−15.459
1.00
23.74
C
ATOM
1471
CG
ARG
B
148
4.731
19.806
−15.393
1.00
24.24
C
ATOM
1472
CD
ARG
B
148
6.127
20.136
−14.793
1.00
24.73
C
ATOM
1473
NE
ARG
B
148
6.742
18.845
−14.478
1.00
26.57
N
ATOM
1474
CZ
ARG
B
148
7.951
18.685
−13.915
1.00
27.32
C
ATOM
1475
NH1
ARG
B
148
8.675
19.731
−13.582
1.00
27.44
N
ATOM
1476
NH2
ARG
B
148
8.397
17.473
−13.660
1.00
26.04
N
ATOM
1477
C
ARG
B
148
1.327
21.521
−15.719
1.00
25.27
C
ATOM
1478
O
ARG
B
148
1.089
22.525
−16.348
1.00
26.12
O
ATOM
1479
N
ALA
B
149
0.732
21.216
−14.560
1.00
27.06
N
ATOM
1480
CA
ALA
B
149
−0.365
22.016
−14.035
1.00
26.93
C
ATOM
1481
CB
ALA
B
149
−1.557
21.094
−13.669
1.00
25.27
C
ATOM
1482
C
ALA
B
149
0.140
22.794
−12.817
1.00
27.42
C
ATOM
1483
O
ALA
B
149
0.668
22.201
−11.875
1.00
26.74
O
ATOM
1484
N
PHE
B
150
−0.011
24.108
−12.845
1.00
28.46
N
ATOM
1485
CA
PHE
B
150
0.541
24.969
−11.779
1.00
31.48
C
ATOM
1486
CB
PHE
B
150
1.476
26.039
−12.378
1.00
30.90
C
ATOM
1487
CG
PHE
B
150
2.683
25.461
−13.023
1.00
31.68
C
ATOM
1488
CD1
PHE
B
150
2.642
25.053
−14.369
1.00
31.92
C
ATOM
1489
CE1
PHE
B
150
3.777
24.515
−14.992
1.00
31.87
C
ATOM
1490
CZ
PHE
B
150
4.963
24.346
−14.254
1.00
31.46
C
ATOM
1491
CE2
PHE
B
150
4.996
24.724
−12.907
1.00
35.16
C
ATOM
1492
CD2
PHE
B
150
3.864
25.283
−12.294
1.00
32.53
C
ATOM
1493
C
PHE
B
150
−0.523
25.681
−10.979
1.00
32.52
C
ATOM
1494
O
PHE
B
150
−1.468
26.207
−11.536
1.00
33.40
O
ATOM
1495
N
THR
B
151
−0.344
25.709
−9.671
1.00
34.98
N
ATOM
1496
CA
THR
B
151
−1.181
26.568
−8.824
1.00
36.44
C
ATOM
1497
CB
THR
B
151
−1.101
26.201
−7.334
1.00
34.71
C
ATOM
1498
OG1
THR
B
151
0.205
26.513
−6.846
1.00
34.94
O
ATOM
1499
CG2
THR
B
151
−1.306
24.732
−7.167
1.00
35.77
C
ATOM
1500
C
THR
B
151
−0.693
27.978
−8.994
1.00
38.85
C
ATOM
1501
O
THR
B
151
0.368
28.212
−9.580
1.00
38.32
O
ATOM
1502
N
GLU
B
152
−1.473
28.927
−8.484
1.00
42.00
N
ATOM
1503
CA
GLU
B
152
−1.139
30.341
−8.597
1.00
44.30
C
ATOM
1504
CB
GLU
B
152
−2.230
31.168
−7.951
1.00
45.82
C
ATOM
1505
CG
GLU
B
152
−3.314
31.579
−8.878
1.00
48.98
C
ATOM
1506
CD
GLU
B
152
−4.434
32.252
−8.130
1.00
51.85
C
ATOM
1507
OE1
GLU
B
152
−4.303
32.390
−6.903
1.00
52.93
O
ATOM
1508
OE2
GLU
B
152
−5.445
32.619
−8.752
1.00
54.82
O
ATOM
1509
C
GLU
B
152
0.186
30.680
−7.952
1.00
44.72
C
ATOM
1510
O
GLU
B
152
0.841
31.641
−8.347
1.00
45.93
O
ATOM
1511
N
GLU
B
153
0.567
29.881
−6.961
1.00
45.12
N
ATOM
1512
CA
GLU
B
153
1.817
30.034
−6.242
1.00
45.17
C
ATOM
1513
CB
GLU
B
153
1.669
29.415
−4.855
1.00
46.29
C
ATOM
1514
CG
GLU
B
153
0.191
29.411
−4.346
1.00
51.61
C
ATOM
1515
CD
GLU
B
153
−0.230
30.758
−3.760
1.00
58.99
C
ATOM
1516
OE1
GLU
B
153
0.679
31.558
−3.403
1.00
61.45
O
ATOM
1517
OE2
GLU
B
153
−1.462
31.023
−3.653
1.00
61.26
O
ATOM
1518
C
GLU
B
153
2.979
29.367
−6.992
1.00
44.04
C
ATOM
1519
O
GLU
B
153
4.143
29.417
−6.535
1.00
43.59
O
ATOM
1520
N
GLY
B
154
2.675
28.728
−8.131
1.00
41.32
N
ATOM
1521
CA
GLY
B
154
3.724
28.130
−8.934
1.00
37.57
C
ATOM
1522
C
GLY
B
154
4.036
26.702
−8.539
1.00
36.03
C
ATOM
1523
O
GLY
B
154
5.054
26.151
−8.942
1.00
35.84
O
ATOM
1524
N
ALA
B
155
3.182
26.072
−7.740
1.00
33.82
N
ATOM
1525
CA
ALA
B
155
3.465
24.653
−7.375
1.00
32.57
C
ATOM
1526
CB
ALA
B
155
2.925
24.332
−6.013
1.00
32.09
C
ATOM
1527
C
ALA
B
155
2.865
23.701
−8.439
1.00
31.21
C
ATOM
1528
O
ALA
B
155
1.803
24.000
−8.987
1.00
32.00
O
ATOM
1529
N
ILE
B
156
3.544
22.579
−8.704
1.00
30.83
N
ATOM
1530
CA
ILE
B
156
3.093
21.593
−9.732
1.00
29.85
C
ATOM
1531
CB
ILE
B
156
4.257
20.837
−10.408
1.00
29.30
C
ATOM
1532
CG1
ILE
B
156
5.185
21.822
−11.123
1.00
30.27
C
ATOM
1533
CD1
ILE
B
156
6.673
21.342
−11.257
1.00
24.87
C
ATOM
1534
CG2
ILE
B
156
3.732
19.766
−11.402
1.00
30.34
C
ATOM
1535
C
ILE
B
156
2.168
20.588
−9.094
1.00
29.67
C
ATOM
1536
O
ILE
B
156
2.477
20.002
−8.031
1.00
28.50
O
ATOM
1537
N
VAL
B
157
0.999
20.401
−9.710
1.00
28.52
N
ATOM
1538
CA
VAL
B
157
0.035
19.457
−9.155
1.00
29.03
C
ATOM
1539
CB
VAL
B
157
−1.210
20.203
−8.605
1.00
28.67
C
ATOM
1540
CG1
VAL
B
157
−0.805
21.289
−7.551
1.00
29.30
C
ATOM
1541
CG2
VAL
B
157
−2.015
20.844
−9.723
1.00
28.06
C
ATOM
1542
C
VAL
B
157
−0.395
18.326
−10.108
1.00
28.97
C
ATOM
1543
O
VAL
B
157
−1.082
17.409
−9.684
1.00
29.30
O
ATOM
1544
N
GLY
B
158
0.037
18.405
−11.383
1.00
28.12
N
ATOM
1545
CA
GLY
B
158
−0.251
17.387
−12.380
1.00
27.35
C
ATOM
1546
C
GLY
B
158
0.715
17.552
−13.554
1.00
26.84
C
ATOM
1547
O
GLY
B
158
1.297
18.625
−13.730
1.00
25.99
O
ATOM
1548
N
GLU
B
159
0.931
16.466
−14.290
1.00
27.11
N
ATOM
1549
CA
GLU
B
159
1.705
16.564
−15.543
1.00
28.08
C
ATOM
1550
CB
GLU
B
159
3.218
16.605
−15.275
1.00
27.46
C
ATOM
1551
CG
GLU
B
159
3.852
15.305
−15.222
1.00
30.14
C
ATOM
1552
CD
GLU
B
159
5.361
15.328
−14.806
1.00
30.39
C
ATOM
1553
OE1
GLU
B
159
5.908
14.231
−14.822
1.00
33.34
O
ATOM
1554
OE2
GLU
B
159
5.948
16.375
−14.425
1.00
32.04
O
ATOM
1555
C
GLU
B
159
1.361
15.466
−16.559
1.00
27.20
C
ATOM
1556
O
GLU
B
159
0.757
14.462
−16.226
1.00
27.15
O
ATOM
1557
N
ILE
B
160
1.694
15.741
−17.823
1.00
27.13
N
ATOM
1558
CA
ILE
B
160
1.587
14.755
−18.883
1.00
27.82
C
ATOM
1559
CB
ILE
B
160
0.478
15.135
−19.891
1.00
28.16
C
ATOM
1560
CG1
ILE
B
160
−0.874
15.160
−19.168
1.00
26.78
C
ATOM
1561
CD1
ILE
B
160
−1.939
15.991
−19.916
1.00
27.37
C
ATOM
1562
CG2
ILE
B
160
0.390
14.107
−21.028
1.00
26.30
C
ATOM
1563
C
ILE
B
160
2.983
14.739
−19.516
1.00
27.85
C
ATOM
1564
O
ILE
B
160
3.518
15.785
−19.859
1.00
26.40
O
ATOM
1565
N
SER
B
161
3.589
13.569
−19.559
1.00
28.39
N
ATOM
1566
CA
SER
B
161
4.891
13.446
−20.194
1.00
30.42
C
ATOM
1567
CB
SER
B
161
6.019
13.335
−19.158
1.00
29.53
C
ATOM
1568
OG
SER
B
161
5.705
12.327
−18.230
1.00
36.43
O
ATOM
1569
C
SER
B
161
4.891
12.216
−21.092
1.00
30.22
C
ATOM
1570
O
SER
B
161
4.212
11.225
−20.815
1.00
29.26
O
ATOM
1571
N
PRO
B
162
5.653
12.292
−22.198
1.00
31.73
N
ATOM
1572
CA
PRO
B
162
5.830
11.168
−23.108
1.00
33.40
C
ATOM
1573
CB
PRO
B
162
6.620
11.787
−24.278
1.00
33.86
C
ATOM
1574
CG
PRO
B
162
6.244
13.258
−24.215
1.00
34.21
C
ATOM
1575
CD
PRO
B
162
6.298
13.505
−22.706
1.00
31.95
C
ATOM
1576
C
PRO
B
162
6.604
10.061
−22.459
1.00
34.81
C
ATOM
1577
O
PRO
B
162
7.528
10.343
−21.712
1.00
35.86
O
ATOM
1578
N
LEU
B
163
6.202
8.819
−22.718
1.00
36.44
N
ATOM
1579
CA
LEU
B
163
6.904
7.630
−22.250
1.00
40.34
C
ATOM
1580
CB
LEU
B
163
5.974
6.431
−22.203
1.00
40.13
C
ATOM
1581
CG
LEU
B
163
4.712
6.559
−21.340
1.00
42.63
C
ATOM
1582
CD1
LEU
B
163
3.831
5.395
−21.657
1.00
43.88
C
ATOM
1583
CD2
LEU
B
163
5.133
6.493
−19.879
1.00
46.62
C
ATOM
1584
C
LEU
B
163
8.064
7.304
−23.202
1.00
42.84
C
ATOM
1585
O
LEU
B
163
7.864
7.201
−24.420
1.00
42.13
O
ATOM
1586
N
PRO
B
164
9.269
7.100
−22.634
1.00
45.85
N
ATOM
1587
CA
PRO
B
164
10.548
6.943
−23.375
1.00
47.72
C
ATOM
1588
CB
PRO
B
164
11.519
6.449
−22.297
1.00
47.76
C
ATOM
1589
CG
PRO
B
164
10.921
6.900
−21.004
1.00
48.29
C
ATOM
1590
CD
PRO
B
164
9.429
6.889
−21.184
1.00
45.64
C
ATOM
1591
C
PRO
B
164
10.428
5.855
−24.422
1.00
49.11
C
ATOM
1592
O
PRO
B
164
10.863
6.022
−25.593
1.00
50.40
O
ATOM
1593
N
SER
B
165
9.806
4.760
−23.985
1.00
50.00
N
ATOM
1594
CA
SER
B
165
9.705
3.526
−24.738
1.00
50.56
C
ATOM
1595
CB
SER
B
165
9.385
2.399
−23.779
1.00
50.90
C
ATOM
1596
OG
SER
B
165
8.001
2.416
−23.479
1.00
51.74
O
ATOM
1597
C
SER
B
165
8.651
3.547
−25.847
1.00
50.55
C
ATOM
1598
O
SER
B
165
8.291
2.493
−26.384
1.00
51.11
O
ATOM
1599
N
PHE
B
166
8.129
4.720
−26.188
1.00
49.55
N
ATOM
1600
CA
PHE
B
166
7.297
4.812
−27.372
1.00
48.18
C
ATOM
1601
CB
PHE
B
166
5.913
5.364
−27.074
1.00
48.72
C
ATOM
1602
CG
PHE
B
166
4.950
4.328
−26.515
1.00
50.30
C
ATOM
1603
CD1
PHE
B
166
3.954
3.777
−27.318
1.00
52.19
C
ATOM
1604
CE1
PHE
B
166
3.045
2.834
−26.811
1.00
53.48
C
ATOM
1605
CZ
PHE
B
166
3.139
2.431
−25.480
1.00
52.84
C
ATOM
1606
CE2
PHE
B
166
4.123
2.993
−24.657
1.00
51.29
C
ATOM
1607
CD2
PHE
B
166
5.020
3.928
−25.178
1.00
51.96
C
ATOM
1608
C
PHE
B
166
8.029
5.623
−28.425
1.00
47.26
C
ATOM
1609
O
PHE
B
166
8.808
6.516
−28.089
1.00
46.10
O
ATOM
1610
N
PRO
B
167
7.814
5.284
−29.715
1.00
46.43
N
ATOM
1611
CA
PRO
B
167
8.561
6.016
−30.748
1.00
45.41
C
ATOM
1612
CB
PRO
B
167
8.412
5.128
−31.984
1.00
45.90
C
ATOM
1613
CG
PRO
B
167
7.006
4.463
−31.803
1.00
46.91
C
ATOM
1614
CD
PRO
B
167
6.894
4.265
−30.275
1.00
45.94
C
ATOM
1615
C
PRO
B
167
7.970
7.416
−30.995
1.00
44.77
C
ATOM
1616
O
PRO
B
167
8.647
8.278
−31.586
1.00
45.20
O
ATOM
1617
N
GLY
B
168
6.729
7.654
−30.545
1.00
42.28
N
ATOM
1618
CA
GLY
B
168
6.100
8.961
−30.762
1.00
38.80
C
ATOM
1619
C
GLY
B
168
4.652
9.017
−30.289
1.00
36.63
C
ATOM
1620
O
GLY
B
168
4.144
8.066
−29.741
1.00
35.45
O
ATOM
1621
N
HIS
B
169
3.998
10.148
−30.497
1.00
35.02
N
ATOM
1622
CA
HIS
B
169
2.574
10.257
−30.146
1.00
34.10
C
ATOM
1623
CB
HIS
B
169
2.430
10.713
−28.678
1.00
32.49
C
ATOM
1624
CG
HIS
B
169
3.112
12.018
−28.401
1.00
30.56
C
ATOM
1625
ND1
HIS
B
169
4.370
12.092
−27.835
1.00
28.47
N
ATOM
1626
CE1
HIS
B
169
4.745
13.365
−27.779
1.00
27.07
C
ATOM
1627
NE2
HIS
B
169
3.758
14.116
−28.244
1.00
26.23
N
ATOM
1628
CD2
HIS
B
169
2.735
13.298
−28.656
1.00
26.61
C
ATOM
1629
C
HIS
B
169
1.995
11.315
−31.050
1.00
33.97
C
ATOM
1630
O
HIS
B
169
2.737
12.034
−31.732
1.00
34.14
O
ATOM
1631
N
THR
B
170
0.672
11.472
−31.016
1.00
33.87
N
ATOM
1632
CA
THR
B
170
0.032
12.498
−31.835
1.00
34.49
C
ATOM
1633
CB
THR
B
170
−0.951
11.856
−32.841
1.00
35.29
C
ATOM
1634
OG1
THR
B
170
−2.138
11.488
−32.134
1.00
38.23
O
ATOM
1635
CG2
THR
B
170
−0.340
10.570
−33.492
1.00
34.81
C
ATOM
1636
C
THR
B
170
−0.744
13.511
−30.985
1.00
33.67
C
ATOM
1637
O
THR
B
170
−0.985
13.293
−29.780
1.00
32.49
O
ATOM
1638
N
ILE
B
171
−1.123
14.609
−31.616
1.00
32.84
N
ATOM
1639
CA
ILE
B
171
−2.019
15.577
−30.986
1.00
33.37
C
ATOM
1640
CB
ILE
B
171
−2.458
16.719
−31.968
1.00
33.99
C
ATOM
1641
CG1
ILE
B
171
−3.157
17.840
−31.181
1.00
33.44
C
ATOM
1642
CD1
ILE
B
171
−3.493
19.085
−31.943
1.00
32.95
C
ATOM
1643
CG2
ILE
B
171
−3.320
16.164
−33.168
1.00
34.46
C
ATOM
1644
C
ILE
B
171
−3.248
14.895
−30.379
1.00
32.88
C
ATOM
1645
O
ILE
B
171
−3.825
15.377
−29.383
1.00
32.45
O
ATOM
1646
N
GLU
B
172
−3.673
13.775
−30.957
1.00
32.23
N
ATOM
1647
CA
GLU
B
172
−4.881
13.160
−30.431
1.00
32.31
C
ATOM
1648
CB
GLU
B
172
−5.553
12.253
−31.434
1.00
33.12
C
ATOM
1649
CG
GLU
B
172
−5.931
12.970
−32.772
1.00
38.08
C
ATOM
1650
CD
GLU
B
172
−7.034
14.096
−32.699
1.00
42.24
C
ATOM
1651
OE1
GLU
B
172
−7.962
14.120
−31.828
1.00
38.52
O
ATOM
1652
OE2
GLU
B
172
−6.976
14.957
−33.605
1.00
44.85
O
ATOM
1653
C
GLU
B
172
−4.575
12.439
−29.117
1.00
31.00
C
ATOM
1654
O
GLU
B
172
−5.427
12.354
−28.221
1.00
29.39
O
ATOM
1655
N
ASP
B
173
−3.364
11.925
−28.994
1.00
29.29
N
ATOM
1656
CA
ASP
B
173
−2.957
11.312
−27.728
1.00
28.81
C
ATOM
1657
CB
ASP
B
173
−1.597
10.654
−27.827
1.00
28.63
C
ATOM
1658
CG
ASP
B
173
−1.591
9.462
−28.738
1.00
30.62
C
ATOM
1659
OD1
ASP
B
173
−2.461
8.581
−28.601
1.00
29.41
O
ATOM
1660
OD2
ASP
B
173
−0.660
9.403
−29.549
1.00
33.78
O
ATOM
1661
C
ASP
B
173
−2.880
12.394
−26.684
1.00
27.22
C
ATOM
1662
O
ASP
B
173
−3.223
12.156
−25.524
1.00
29.09
O
ATOM
1663
N
VAL
B
174
−2.390
13.553
−27.090
1.00
26.94
N
ATOM
1664
CA
VAL
B
174
−2.212
14.683
−26.195
1.00
27.05
C
ATOM
1665
CB
VAL
B
174
−1.431
15.823
−26.851
1.00
27.03
C
ATOM
1666
CG1
VAL
B
174
−1.453
17.050
−25.954
1.00
27.31
C
ATOM
1667
CG2
VAL
B
174
0.046
15.419
−27.117
1.00
28.19
C
ATOM
1668
C
VAL
B
174
−3.594
15.143
−25.715
1.00
27.12
C
ATOM
1669
O
VAL
B
174
−3.845
15.343
−24.519
1.00
24.96
O
ATOM
1670
N
LYS
B
175
−4.523
15.267
−26.650
1.00
25.83
N
ATOM
1671
CA
LYS
B
175
−5.874
15.649
−26.236
1.00
26.01
C
ATOM
1672
CB
LYS
B
175
−6.749
15.904
−27.458
1.00
26.17
C
ATOM
1673
CG
LYS
B
175
−6.739
17.324
−27.834
1.00
30.35
C
ATOM
1674
CD
LYS
B
175
−6.102
17.480
−29.128
1.00
38.18
C
ATOM
1675
CE
LYS
B
175
−7.142
17.623
−30.145
1.00
37.08
C
ATOM
1676
NZ
LYS
B
175
−7.550
19.051
−30.104
1.00
42.61
N
ATOM
1677
C
LYS
B
175
−6.542
14.661
−25.292
1.00
25.19
C
ATOM
1678
O
LYS
B
175
−7.220
15.074
−24.345
1.00
26.66
O
ATOM
1679
N
ASN
B
176
−6.414
13.358
−25.543
1.00
23.95
N
ATOM
1680
CA
ASN
B
176
−6.974
12.363
−24.636
1.00
23.14
C
ATOM
1681
CB
ASN
B
176
−6.557
10.938
−25.058
1.00
24.94
C
ATOM
1682
CG
ASN
B
176
−7.206
10.470
−26.375
1.00
26.18
C
ATOM
1683
OD1
ASN
B
176
−8.233
11.005
−26.802
1.00
29.88
O
ATOM
1684
ND2
ASN
B
176
−6.606
9.452
−26.994
1.00
29.47
N
ATOM
1685
C
ASN
B
176
−6.446
12.572
−23.184
1.00
23.69
C
ATOM
1686
O
ASN
B
176
−7.234
12.592
−22.206
1.00
22.87
O
ATOM
1687
N
ALA
B
177
−5.119
12.682
−23.064
1.00
22.91
N
ATOM
1688
CA
ALA
B
177
−4.442
12.879
−21.767
1.00
23.94
C
ATOM
1689
CB
ALA
B
177
−2.902
12.772
−21.924
1.00
25.51
C
ATOM
1690
C
ALA
B
177
−4.806
14.179
−21.085
1.00
22.98
C
ATOM
1691
O
ALA
B
177
−4.986
14.189
−19.863
1.00
23.61
O
ATOM
1692
N
ILE
B
178
−4.923
15.267
−21.832
1.00
23.01
N
ATOM
1693
CA
ILE
B
178
−5.391
16.554
−21.279
1.00
24.94
C
ATOM
1694
CB
ILE
B
178
−5.277
17.726
−22.315
1.00
23.97
C
ATOM
1695
CG1
ILE
B
178
−3.783
18.066
−22.574
1.00
25.98
C
ATOM
1696
CD1
ILE
B
178
−3.585
19.202
−23.573
1.00
27.04
C
ATOM
1697
CG2
ILE
B
178
−5.957
18.997
−21.792
1.00
24.69
C
ATOM
1698
C
ILE
B
178
−6.823
16.495
−20.696
1.00
25.65
C
ATOM
1699
O
ILE
B
178
−7.076
16.967
−19.583
1.00
26.20
O
ATOM
1700
N
GLY
B
179
−7.741
15.872
−21.421
1.00
24.86
N
ATOM
1701
CA
GLY
B
179
−9.067
15.626
−20.868
1.00
25.64
C
ATOM
1702
C
GLY
B
179
−9.022
14.827
−19.572
1.00
26.53
C
ATOM
1703
O
GLY
B
179
−9.759
15.131
−18.648
1.00
27.05
O
ATOM
1704
N
VAL
B
180
−8.181
13.778
−19.488
1.00
27.64
N
ATOM
1705
CA
VAL
B
180
−8.096
12.989
−18.230
1.00
26.49
C
ATOM
1706
CB
VAL
B
180
−7.242
11.709
−18.330
1.00
27.34
C
ATOM
1707
CG1
VAL
B
180
−6.987
11.099
−16.920
1.00
27.00
C
ATOM
1708
CG2
VAL
B
180
−7.918
10.674
−19.251
1.00
26.03
C
ATOM
1709
C
VAL
B
180
−7.571
13.854
−17.088
1.00
26.25
C
ATOM
1710
O
VAL
B
180
−8.148
13.836
−15.964
1.00
26.42
O
ATOM
1711
N
LEU
B
181
−6.511
14.607
−17.353
1.00
25.79
N
ATOM
1712
CA
LEU
B
181
−5.949
15.522
−16.345
1.00
26.04
C
ATOM
1713
CB
LEU
B
181
−4.587
16.119
−16.807
1.00
26.20
C
ATOM
1714
CG
LEU
B
181
−3.936
17.200
−15.923
1.00
26.41
C
ATOM
1715
CD1
LEU
B
181
−3.517
16.667
−14.581
1.00
22.34
C
ATOM
1716
CD2
LEU
B
181
−2.717
17.769
−16.620
1.00
24.16
C
ATOM
1717
C
LEU
B
181
−6.890
16.637
−15.881
1.00
26.68
C
ATOM
1718
O
LEU
B
181
−7.083
16.841
−14.654
1.00
26.04
O
ATOM
1719
N
ILE
B
182
−7.471
17.363
−16.835
1.00
26.09
N
ATOM
1720
CA
ILE
B
182
−8.388
18.436
−16.532
1.00
25.74
C
ATOM
1721
CB
ILE
B
182
−8.861
19.141
−17.805
1.00
26.51
C
ATOM
1722
CG1
ILE
B
182
−7.723
19.973
−18.396
1.00
24.82
C
ATOM
1723
CD1
ILE
B
182
−8.143
20.834
−19.674
1.00
25.81
C
ATOM
1724
CG2
ILE
B
182
−10.124
20.002
−17.515
1.00
27.97
C
ATOM
1725
C
ILE
B
182
−9.608
17.916
−15.775
1.00
26.63
C
ATOM
1726
O
ILE
B
182
−10.110
18.623
−14.867
1.00
26.56
O
ATOM
1727
N
GLY
B
183
−10.084
16.717
−16.143
1.00
25.84
N
ATOM
1728
CA
GLY
B
183
−11.280
16.150
−15.538
1.00
26.48
C
ATOM
1729
C
GLY
B
183
−10.999
15.788
−14.062
1.00
26.93
C
ATOM
1730
O
GLY
B
183
−11.881
15.926
−13.212
1.00
25.70
O
ATOM
1731
N
GLY
B
184
−9.780
15.311
−13.765
1.00
24.71
N
ATOM
1732
CA
GLY
B
184
−9.412
14.978
−12.383
1.00
27.81
C
ATOM
1733
C
GLY
B
184
−9.317
16.235
−11.536
1.00
27.95
C
ATOM
1734
O
GLY
B
184
−9.831
16.263
−10.411
1.00
29.12
O
ATOM
1735
N
LEU
B
185
−8.698
17.278
−12.075
1.00
27.43
N
ATOM
1736
CA
LEU
B
185
−8.556
18.574
−11.373
1.00
26.86
C
ATOM
1737
CB
LEU
B
185
−7.718
19.529
−12.199
1.00
26.76
C
ATOM
1738
CG
LEU
B
185
−6.203
19.174
−12.300
1.00
25.88
C
ATOM
1739
CD1
LEU
B
185
−5.629
20.023
−13.351
1.00
24.14
C
ATOM
1740
CD2
LEU
B
185
−5.470
19.340
−10.922
1.00
24.41
C
ATOM
1741
C
LEU
B
185
−9.938
19.230
−11.118
1.00
28.13
C
ATOM
1742
O
LEU
B
185
−10.205
19.698
−10.025
1.00
27.27
O
ATOM
1743
N
GLU
B
186
−10.779
19.302
−12.148
1.00
26.45
N
ATOM
1744
CA
GLU
B
186
−12.176
19.722
−12.017
1.00
28.86
C
ATOM
1745
CB
GLU
B
186
−12.913
19.596
−13.378
1.00
28.42
C
ATOM
1746
CG
GLU
B
186
−12.605
20.641
−14.405
1.00
31.60
C
ATOM
1747
CD
GLU
B
186
−13.303
20.308
−15.787
1.00
33.01
C
ATOM
1748
OE1
GLU
B
186
−13.747
19.131
−16.049
1.00
34.53
O
ATOM
1749
OE2
GLU
B
186
−13.393
21.253
−16.571
1.00
35.62
O
ATOM
1750
C
GLU
B
186
−12.918
18.895
−10.986
1.00
28.14
C
ATOM
1751
O
GLU
B
186
−13.594
19.470
−10.152
1.00
29.83
O
ATOM
1752
N
TRP
B
187
−12.839
17.557
−11.049
1.00
27.79
N
ATOM
1753
CA
TRP
B
187
−13.520
16.713
−10.106
1.00
29.99
C
ATOM
1754
CB
TRP
B
187
−13.187
15.237
−10.335
1.00
30.68
C
ATOM
1755
CG
TRP
B
187
−13.585
14.307
−9.227
1.00
34.71
C
ATOM
1756
CD1
TRP
B
187
−12.794
13.848
−8.167
1.00
35.56
C
ATOM
1757
NE1
TRP
B
187
−13.496
12.989
−7.373
1.00
36.67
N
ATOM
1758
CE2
TRP
B
187
−14.761
12.866
−7.899
1.00
38.56
C
ATOM
1759
CD2
TRP
B
187
−14.847
13.686
−9.060
1.00
35.87
C
ATOM
1760
CE3
TRP
B
187
−16.049
13.746
−9.774
1.00
34.89
C
ATOM
1761
CZ3
TRP
B
187
−17.098
13.013
−9.333
1.00
37.19
C
ATOM
1762
CH2
TRP
B
187
−16.998
12.205
−8.162
1.00
37.23
C
ATOM
1763
CZ2
TRP
B
187
−15.835
12.128
−7.435
1.00
38.41
C
ATOM
1764
C
TRP
B
187
−13.187
17.105
−8.646
1.00
29.34
C
ATOM
1765
O
TRP
B
187
−14.051
16.999
−7.782
1.00
26.13
O
ATOM
1766
N
ASN
B
188
−11.933
17.528
−8.418
1.00
29.25
N
ATOM
1767
CA
ASN
B
188
−11.426
18.015
−7.112
1.00
30.10
C
ATOM
1768
CB
ASN
B
188
−9.922
17.678
−6.960
1.00
30.98
C
ATOM
1769
CG
ASN
B
188
−9.691
16.346
−6.270
1.00
28.83
C
ATOM
1770
OD1
ASN
B
188
−10.634
15.706
−5.865
1.00
30.25
O
ATOM
1771
ND2
ASN
B
188
−8.427
15.909
−6.166
1.00
27.24
N
ATOM
1772
C
ASN
B
188
−11.645
19.483
−6.856
1.00
30.32
C
ATOM
1773
O
ASN
B
188
−10.987
20.074
−6.005
1.00
31.38
O
ATOM
1774
N
ASP
B
189
−12.578
20.083
−7.576
1.00
31.64
N
ATOM
1775
CA
ASP
B
189
−12.989
21.492
−7.404
1.00
31.66
C
ATOM
1776
CB
ASP
B
189
−13.739
21.693
−6.056
1.00
33.12
C
ATOM
1777
CG
ASP
B
189
−15.040
20.898
−6.016
1.00
37.29
C
ATOM
1778
OD1
ASP
B
189
−15.825
21.100
−6.970
1.00
38.57
O
ATOM
1779
OD2
ASP
B
189
−15.261
20.060
−5.084
1.00
40.54
O
ATOM
1780
C
ASP
B
189
−11.916
22.524
−7.602
1.00
32.43
C
ATOM
1781
O
ASP
B
189
−11.978
23.619
−7.028
1.00
30.55
O
ATOM
1782
N
ASN
B
190
−10.930
22.197
−8.443
1.00
30.63
N
ATOM
1783
CA
ASN
B
190
−10.001
23.204
−8.912
1.00
30.98
C
ATOM
1784
CB
ASN
B
190
−8.642
22.559
−9.244
1.00
29.41
C
ATOM
1785
CG
ASN
B
190
−8.039
21.837
−8.058
1.00
27.80
C
ATOM
1786
OD1
ASN
B
190
−7.559
22.467
−7.100
1.00
28.21
O
ATOM
1787
ND2
ASN
B
190
−8.069
20.507
−8.096
1.00
24.72
N
ATOM
1788
C
ASN
B
190
−10.590
23.894
−10.133
1.00
31.62
C
ATOM
1789
O
ASN
B
190
−11.320
23.270
−10.893
1.00
31.86
O
ATOM
1790
N
THR
B
191
−10.304
25.184
−10.298
1.00
32.87
N
ATOM
1791
CA
THR
B
191
−10.634
25.916
−11.509
1.00
34.75
C
ATOM
1792
CB
THR
B
191
−10.945
27.380
−11.169
1.00
35.55
C
ATOM
1793
OG1
THR
B
191
−12.062
27.415
−10.261
1.00
37.47
O
ATOM
1794
CG2
THR
B
191
−11.328
28.148
−12.411
1.00
37.42
C
ATOM
1795
C
THR
B
191
−9.437
25.837
−12.451
1.00
34.83
C
ATOM
1796
O
THR
B
191
−8.304
26.214
−12.070
1.00
35.55
O
ATOM
1797
N
VAL
B
192
−9.681
25.329
−13.661
1.00
34.58
N
ATOM
1798
CA
VAL
B
192
−8.604
25.019
−14.605
1.00
34.33
C
ATOM
1799
CB
VAL
B
192
−8.616
23.526
−15.076
1.00
33.53
C
ATOM
1800
CG1
VAL
B
192
−7.387
23.231
−16.021
1.00
34.55
C
ATOM
1801
CG2
VAL
B
192
−8.565
22.595
−13.908
1.00
31.05
C
ATOM
1802
C
VAL
B
192
−8.607
25.959
−15.788
1.00
35.32
C
ATOM
1803
O
VAL
B
192
−9.593
26.041
−16.515
1.00
35.56
O
ATOM
1804
N
ARG
B
193
−7.495
26.665
−15.987
1.00
35.84
N
ATOM
1805
CA
ARG
B
193
−7.252
27.415
−17.216
1.00
37.58
C
ATOM
1806
CB
ARG
B
193
−6.868
28.876
−16.900
1.00
37.82
C
ATOM
1807
CG
ARG
B
193
−8.073
29.733
−16.543
1.00
42.79
C
ATOM
1808
CD
ARG
B
193
−7.707
31.011
−15.825
1.00
50.50
C
ATOM
1809
NE
ARG
B
193
−8.639
31.231
−14.712
1.00
55.68
N
ATOM
1810
CZ
ARG
B
193
−8.545
30.633
−13.517
1.00
58.91
C
ATOM
1811
NH1
ARG
B
193
−7.546
29.763
−13.241
1.00
59.58
N
ATOM
1812
NH2
ARG
B
193
−9.454
30.908
−12.589
1.00
59.65
N
ATOM
1813
C
ARG
B
193
−6.111
26.775
−18.010
1.00
37.54
C
ATOM
1814
O
ARG
B
193
−5.287
26.058
−17.449
1.00
36.53
O
ATOM
1815
N
VAL
B
194
−6.055
27.093
−19.306
1.00
37.96
N
ATOM
1816
CA
VAL
B
194
−5.076
26.501
−20.232
1.00
37.55
C
ATOM
1817
CB
VAL
B
194
−5.834
25.611
−21.268
1.00
38.83
C
ATOM
1818
CG1
VAL
B
194
−5.025
25.322
−22.493
1.00
40.07
C
ATOM
1819
CG2
VAL
B
194
−6.213
24.302
−20.615
1.00
35.70
C
ATOM
1820
C
VAL
B
194
−4.301
27.662
−20.840
1.00
37.68
C
ATOM
1821
O
VAL
B
194
−4.886
28.739
−21.085
1.00
36.58
O
ATOM
1822
N
SER
B
195
−2.984
27.496
−21.020
1.00
36.31
N
ATOM
1823
CA
SER
B
195
−2.171
28.555
−21.584
1.00
35.49
C
ATOM
1824
CB
SER
B
195
−0.710
28.091
−21.710
1.00
35.57
C
ATOM
1825
OG
SER
B
195
−0.564
27.142
−22.752
1.00
33.21
O
ATOM
1826
C
SER
B
195
−2.770
28.982
−22.950
1.00
36.06
C
ATOM
1827
O
SER
B
195
−3.429
28.171
−23.634
1.00
34.56
O
ATOM
1828
N
LYS
B
196
−2.597
30.252
−23.306
1.00
36.20
N
ATOM
1829
CA
LYS
B
196
−3.116
30.760
−24.576
1.00
37.88
C
ATOM
1830
CB
LYS
B
196
−2.919
32.264
−24.713
1.00
38.69
C
ATOM
1831
CG
LYS
B
196
−3.804
33.084
−23.759
1.00
43.56
C
ATOM
1832
CD
LYS
B
196
−3.659
34.583
−24.100
1.00
49.67
C
ATOM
1833
CE
LYS
B
196
−4.059
35.504
−22.919
1.00
52.45
C
ATOM
1834
NZ
LYS
B
196
−2.985
35.632
−21.851
1.00
53.35
N
ATOM
1835
C
LYS
B
196
−2.448
30.060
−25.745
1.00
37.09
C
ATOM
1836
O
LYS
B
196
−3.068
29.898
−26.784
1.00
37.20
O
ATOM
1837
N
THR
B
197
−1.189
29.652
−25.576
1.00
36.42
N
ATOM
1838
CA
THR
B
197
−0.530
28.848
−26.612
1.00
36.69
C
ATOM
1839
CB
THR
B
197
0.992
28.707
−26.426
1.00
36.21
C
ATOM
1840
OG1
THR
B
197
1.260
28.069
−25.162
1.00
38.36
O
ATOM
1841
CG2
THR
B
197
1.678
30.046
−26.531
1.00
38.13
C
ATOM
1842
C
THR
B
197
−1.122
27.451
−26.718
1.00
35.35
C
ATOM
1843
O
THR
B
197
−1.297
26.953
−27.793
1.00
35.92
O
ATOM
1844
N
LEU
B
198
−1.418
26.809
−25.601
1.00
36.53
N
ATOM
1845
CA
LEU
B
198
−2.068
25.516
−25.657
1.00
36.92
C
ATOM
1846
CB
LEU
B
198
−2.180
24.876
−24.275
1.00
36.99
C
ATOM
1847
CG
LEU
B
198
−1.098
23.952
−23.729
1.00
33.23
C
ATOM
1848
CD1
LEU
B
198
−1.449
23.661
−22.274
1.00
33.04
C
ATOM
1849
CD2
LEU
B
198
−1.072
22.672
−24.603
1.00
29.08
C
ATOM
1850
C
LEU
B
198
−3.467
25.655
−26.256
1.00
39.11
C
ATOM
1851
O
LEU
B
198
−3.850
24.850
−27.092
1.00
38.44
O
ATOM
1852
N
GLN
B
199
−4.252
26.646
−25.830
1.00
41.80
N
ATOM
1853
CA
GLN
B
199
−5.572
26.806
−26.478
1.00
45.46
C
ATOM
1854
CB
GLN
B
199
−6.537
27.763
−25.752
1.00
45.75
C
ATOM
1855
CG
GLN
B
199
−6.008
29.085
−25.299
1.00
49.36
C
ATOM
1856
CD
GLN
B
199
−6.963
29.806
−24.295
1.00
50.29
C
ATOM
1857
OE1
GLN
B
199
−7.702
29.163
−23.540
1.00
54.54
O
ATOM
1858
NE2
GLN
B
199
−6.935
31.148
−24.303
1.00
55.26
N
ATOM
1859
C
GLN
B
199
−5.467
27.120
−27.970
1.00
45.02
C
ATOM
1860
O
GLN
B
199
−6.285
26.660
−28.731
1.00
45.85
O
ATOM
1861
N
ARG
B
200
−4.444
27.854
−28.388
1.00
45.93
N
ATOM
1862
CA
ARG
B
200
−4.258
28.142
−29.827
1.00
47.16
C
ATOM
1863
CB
ARG
B
200
−3.270
29.269
−30.062
1.00
47.37
C
ATOM
1864
CG
ARG
B
200
−2.927
29.415
−31.545
1.00
50.46
C
ATOM
1865
CD
ARG
B
200
−2.055
30.607
−31.841
1.00
54.16
C
ATOM
1866
NE
ARG
B
200
−1.831
30.736
−33.284
1.00
58.36
N
ATOM
1867
CZ
ARG
B
200
−0.821
31.406
−33.853
1.00
60.38
C
ATOM
1868
NH1
ARG
B
200
0.099
32.036
−33.117
1.00
59.70
N
ATOM
1869
NH2
ARG
B
200
−0.728
31.438
−35.178
1.00
61.24
N
ATOM
1870
C
ARG
B
200
−3.823
26.940
−30.663
1.00
47.23
C
ATOM
1871
O
ARG
B
200
−4.319
26.733
−31.775
1.00
47.03
O
ATOM
1872
N
PHE
B
201
−2.886
26.162
−30.134
1.00
47.51
N
ATOM
1873
CA
PHE
B
201
−2.210
25.130
−30.932
1.00
47.97
C
ATOM
1874
CB
PHE
B
201
−0.697
25.178
−30.715
1.00
46.65
C
ATOM
1875
CG
PHE
B
201
−0.060
26.428
−31.243
1.00
46.30
C
ATOM
1876
CD1
PHE
B
201
−0.158
26.752
−32.596
1.00
46.65
C
ATOM
1877
CE1
PHE
B
201
0.426
27.888
−33.096
1.00
44.92
C
ATOM
1878
CZ
PHE
B
201
1.120
28.730
−32.244
1.00
48.15
C
ATOM
1879
CE2
PHE
B
201
1.217
28.419
−30.878
1.00
46.43
C
ATOM
1880
CD2
PHE
B
201
0.632
27.280
−30.399
1.00
44.50
C
ATOM
1881
C
PHE
B
201
−2.753
23.736
−30.726
1.00
48.74
C
ATOM
1882
O
PHE
B
201
−2.597
22.864
−31.593
1.00
48.64
O
ATOM
1883
N
ALA
B
202
−3.370
23.508
−29.576
1.00
50.44
N
ATOM
1884
CA
ALA
B
202
−4.033
22.247
−29.341
1.00
53.42
C
ATOM
1885
CB
ALA
B
202
−3.728
21.709
−27.948
1.00
52.66
C
ATOM
1886
C
ALA
B
202
−5.543
22.370
−29.606
1.00
54.73
C
ATOM
1887
O
ALA
B
202
−6.238
21.374
−29.502
1.00
56.24
O
ATOM
1888
N
TRP
B
203
−6.011
23.586
−29.956
1.00
56.29
N
ATOM
1889
CA
TRP
B
203
−7.395
23.933
−30.455
1.00
56.94
C
ATOM
1890
CB
TRP
B
203
−8.380
24.142
−29.301
1.00
58.23
C
ATOM
1891
CG
TRP
B
203
−8.552
22.939
−28.504
1.00
59.56
C
ATOM
1892
CD1
TRP
B
203
−9.345
21.864
−28.804
1.00
61.53
C
ATOM
1893
NE1
TRP
B
203
−9.230
20.906
−27.822
1.00
62.77
N
ATOM
1894
CE2
TRP
B
203
−8.340
21.347
−26.873
1.00
62.01
C
ATOM
1895
CD2
TRP
B
203
−7.901
22.632
−27.269
1.00
61.50
C
ATOM
1896
CE3
TRP
B
203
−6.983
23.310
−26.460
1.00
62.77
C
ATOM
1897
CZ3
TRP
B
203
−6.547
22.698
−25.292
1.00
61.79
C
ATOM
1898
CH2
TRP
B
203
−7.013
21.418
−24.918
1.00
61.03
C
ATOM
1899
CZ2
TRP
B
203
−7.898
20.730
−25.690
1.00
60.64
C
ATOM
1900
C
TRP
B
203
−7.437
25.187
−31.366
1.00
57.77
C
ATOM
1901
O
TRP
B
203
−8.201
26.147
−31.186
1.00
57.76
O
ATOM
1902
OXT
TRP
B
203
−6.692
25.319
−32.339
1.00
58.42
O
ATOM
1903
N
HIS
D
56
34.592
2.339
9.216
1.00
64.66
N
ATOM
1904
CA
HIS
D
56
34.345
2.715
10.649
1.00
64.55
C
ATOM
1905
CB
HIS
D
56
35.029
1.705
11.625
1.00
65.47
C
ATOM
1906
CG
HIS
D
56
36.531
1.764
11.637
1.00
68.06
C
ATOM
1907
ND1
HIS
D
56
37.317
1.022
10.777
1.00
71.84
N
ATOM
1908
CE1
HIS
D
56
38.593
1.276
11.018
1.00
72.28
C
ATOM
1909
NE2
HIS
D
56
38.664
2.154
12.006
1.00
70.72
N
ATOM
1910
CD2
HIS
D
56
37.390
2.469
12.415
1.00
69.56
C
ATOM
1911
C
HIS
D
56
34.649
4.212
10.979
1.00
63.35
C
ATOM
1912
O
HIS
D
56
35.235
4.560
12.024
1.00
63.93
O
ATOM
1913
N
HIS
D
57
34.212
5.104
10.095
1.00
61.01
N
ATOM
1914
CA
HIS
D
57
34.497
6.533
10.244
1.00
58.95
C
ATOM
1915
CB
HIS
D
57
35.769
6.906
9.444
1.00
59.82
C
ATOM
1916
CG
HIS
D
57
36.783
5.797
9.346
1.00
62.98
C
ATOM
1917
ND1
HIS
D
57
36.602
4.683
8.545
1.00
66.61
N
ATOM
1918
CE1
HIS
D
57
37.641
3.872
8.672
1.00
67.08
C
ATOM
1919
NE2
HIS
D
57
38.490
4.417
9.528
1.00
67.51
N
ATOM
1920
CD2
HIS
D
57
37.979
5.622
9.961
1.00
66.43
C
ATOM
1921
C
HIS
D
57
33.300
7.267
9.654
1.00
55.91
C
ATOM
1922
O
HIS
D
57
32.887
6.931
8.536
1.00
56.18
O
ATOM
1923
N
HIS
D
58
32.694
8.230
10.355
1.00
51.42
N
ATOM
1924
CA
HIS
D
58
31.740
9.014
9.589
1.00
47.26
C
ATOM
1925
CB
HIS
D
58
30.404
9.340
10.238
1.00
48.71
C
ATOM
1926
CG
HIS
D
58
29.369
9.596
9.188
1.00
54.11
C
ATOM
1927
ND1
HIS
D
58
28.703
10.793
9.049
1.00
58.72
N
ATOM
1928
CE1
HIS
D
58
27.920
10.740
7.977
1.00
61.41
C
ATOM
1929
NE2
HIS
D
58
28.103
9.573
7.379
1.00
60.54
N
ATOM
1930
CD2
HIS
D
58
29.009
8.842
8.112
1.00
59.27
C
ATOM
1931
C
HIS
D
58
32.286
10.247
8.894
1.00
42.65
C
ATOM
1932
O
HIS
D
58
33.093
10.973
9.453
1.00
40.85
O
ATOM
1933
N
HIS
D
59
31.787
10.482
7.680
1.00
37.62
N
ATOM
1934
CA
HIS
D
59
32.120
11.671
6.915
1.00
33.38
C
ATOM
1935
CB
HIS
D
59
31.913
11.451
5.408
1.00
31.80
C
ATOM
1936
CG
HIS
D
59
32.889
10.495
4.815
1.00
30.00
C
ATOM
1937
ND1
HIS
D
59
34.093
10.904
4.271
1.00
26.51
N
ATOM
1938
CE1
HIS
D
59
34.761
9.837
3.865
1.00
28.12
C
ATOM
1939
NE2
HIS
D
59
34.015
8.765
4.067
1.00
27.17
N
ATOM
1940
CD2
HIS
D
59
32.845
9.148
4.679
1.00
28.48
C
ATOM
1941
C
HIS
D
59
31.362
12.894
7.336
1.00
32.02
C
ATOM
1942
O
HIS
D
59
31.849
13.970
7.117
1.00
32.51
O
ATOM
1943
N
MET
D
60
30.150
12.765
7.885
1.00
31.80
N
ATOM
1944
CA
MET
D
60
29.369
13.977
8.243
1.00
31.40
C
ATOM
1945
CB
MET
D
60
27.889
13.902
7.828
1.00
32.22
C
ATOM
1946
CG
MET
D
60
27.617
13.875
6.267
1.00
37.88
C
ATOM
1947
SD
MET
D
60
27.808
15.376
5.183
1.00
44.72
S
ATOM
1948
CE
MET
D
60
26.475
16.498
5.654
1.00
45.45
C
ATOM
1949
C
MET
D
60
29.501
14.277
9.760
1.00
29.90
C
ATOM
1950
O
MET
D
60
29.577
13.361
10.575
1.00
28.64
O
ATOM
1951
N
SER
D
61
29.535
15.557
10.109
1.00
30.29
N
ATOM
1952
CA
SER
D
61
29.588
15.983
11.499
1.00
30.76
C
ATOM
1953
CB
SER
D
61
29.925
17.460
11.570
1.00
30.74
C
ATOM
1954
OG
SER
D
61
28.848
18.250
11.070
1.00
29.96
O
ATOM
1955
C
SER
D
61
28.253
15.750
12.221
1.00
32.49
C
ATOM
1956
O
SER
D
61
28.206
15.601
13.460
1.00
32.22
O
ATOM
1957
N
GLY
D
62
27.173
15.744
11.452
1.00
33.25
N
ATOM
1958
CA
GLY
D
62
25.831
15.442
11.967
1.00
34.91
C
ATOM
1959
C
GLY
D
62
24.939
15.316
10.728
1.00
37.02
C
ATOM
1960
O
GLY
D
62
25.415
15.463
9.602
1.00
36.12
O
ATOM
1961
N
GLU
D
63
23.649
15.056
10.903
1.00
38.27
N
ATOM
1962
CA
GLU
D
63
22.778
15.047
9.723
1.00
41.05
C
ATOM
1963
CB
GLU
D
63
22.745
13.647
9.064
1.00
41.25
C
ATOM
1964
CG
GLU
D
63
21.929
12.590
9.806
1.00
44.88
C
ATOM
1965
CD
GLU
D
63
22.092
11.175
9.212
1.00
45.68
C
ATOM
1966
OE1
GLU
D
63
21.509
10.883
8.130
1.00
50.03
O
ATOM
1967
OE2
GLU
D
63
22.789
10.347
9.848
1.00
51.89
O
ATOM
1968
C
GLU
D
63
21.359
15.560
10.053
1.00
40.41
C
ATOM
1969
O
GLU
D
63
20.917
15.481
11.203
1.00
39.58
O
ATOM
1970
N
LYS
D
64
20.675
16.079
9.030
1.00
39.97
N
ATOM
1971
CA
LYS
D
64
19.253
16.453
9.124
1.00
39.55
C
ATOM
1972
CB
LYS
D
64
18.855
17.312
7.933
1.00
38.27
C
ATOM
1973
CG
LYS
D
64
19.498
18.676
7.978
1.00
37.25
C
ATOM
1974
CD
LYS
D
64
19.352
19.392
6.699
1.00
37.42
C
ATOM
1975
CE
LYS
D
64
19.582
20.874
6.890
1.00
40.00
C
ATOM
1976
NZ
LYS
D
64
19.659
21.591
5.597
1.00
41.12
N
ATOM
1977
C
LYS
D
64
18.447
15.173
9.226
1.00
39.27
C
ATOM
1978
O
LYS
D
64
18.598
14.260
8.428
1.00
40.43
O
ATOM
1979
N
THR
D
65
17.612
15.062
10.241
1.00
40.07
N
ATOM
1980
CA
THR
D
65
17.000
13.756
10.492
1.00
40.21
C
ATOM
1981
CB
THR
D
65
17.075
13.371
11.988
1.00
40.76
C
ATOM
1982
OG1
THR
D
65
16.660
14.502
12.769
1.00
42.99
O
ATOM
1983
CG2
THR
D
65
18.532
12.999
12.379
1.00
42.94
C
ATOM
1984
C
THR
D
65
15.543
13.715
10.026
1.00
38.61
C
ATOM
1985
O
THR
D
65
14.950
12.653
9.998
1.00
38.55
O
ATOM
1986
N
VAL
D
66
14.976
14.875
9.685
1.00
37.32
N
ATOM
1987
CA
VAL
D
66
13.577
14.945
9.213
1.00
36.16
C
ATOM
1988
CB
VAL
D
66
12.658
15.607
10.304
1.00
37.17
C
ATOM
1989
CG1
VAL
D
66
11.174
15.588
9.875
1.00
36.22
C
ATOM
1990
CG2
VAL
D
66
12.797
14.868
11.625
1.00
37.85
C
ATOM
1991
C
VAL
D
66
13.414
15.723
7.913
1.00
34.38
C
ATOM
1992
O
VAL
D
66
13.926
16.848
7.791
1.00
33.99
O
ATOM
1993
N
VAL
D
67
12.646
15.159
6.969
1.00
34.25
N
ATOM
1994
CA
VAL
D
67
12.330
15.843
5.687
1.00
33.06
C
ATOM
1995
CB
VAL
D
67
11.704
14.865
4.636
1.00
33.93
C
ATOM
1996
CG1
VAL
D
67
11.168
15.648
3.370
1.00
30.51
C
ATOM
1997
CG2
VAL
D
67
12.691
13.730
4.262
1.00
34.10
C
ATOM
1998
C
VAL
D
67
11.411
17.069
5.921
1.00
32.76
C
ATOM
1999
O
VAL
D
67
10.519
17.011
6.756
1.00
33.03
O
ATOM
2000
N
CYS
D
68
11.676
18.179
5.236
1.00
32.16
N
ATOM
2001
CA
CYS
D
68
10.907
19.397
5.407
1.00
32.44
C
ATOM
2002
CB
CYS
D
68
11.597
20.575
4.774
1.00
31.82
C
ATOM
2003
SG
CYS
D
68
10.774
22.098
5.030
1.00
33.61
S
ATOM
2004
C
CYS
D
68
9.550
19.203
4.723
1.00
32.88
C
ATOM
2005
O
CYS
D
68
9.476
19.154
3.491
1.00
30.62
O
ATOM
2006
N
LYS
D
69
8.484
19.090
5.519
1.00
33.15
N
ATOM
2007
CA
LYS
D
69
7.172
18.858
4.910
1.00
34.88
C
ATOM
2008
CB
LYS
D
69
6.157
18.270
5.917
1.00
35.34
C
ATOM
2009
CG
LYS
D
69
5.811
19.205
7.044
1.00
36.65
C
ATOM
2010
CD
LYS
D
69
4.712
18.618
7.967
1.00
37.03
C
ATOM
2011
CE
LYS
D
69
3.257
18.968
7.480
1.00
37.27
C
ATOM
2012
NZ
LYS
D
69
2.907
20.446
7.579
1.00
36.89
N
ATOM
2013
C
LYS
D
69
6.676
20.095
4.180
1.00
35.15
C
ATOM
2014
O
LYS
D
69
5.946
19.975
3.181
1.00
35.27
O
ATOM
2015
N
HIS
D
70
7.104
21.288
4.605
1.00
37.08
N
ATOM
2016
CA
HIS
D
70
6.813
22.498
3.813
1.00
38.20
C
ATOM
2017
CB
HIS
D
70
7.195
23.768
4.561
1.00
39.21
C
ATOM
2018
CG
HIS
D
70
6.402
23.956
5.819
1.00
43.73
C
ATOM
2019
ND1
HIS
D
70
6.986
24.109
7.059
1.00
46.35
N
ATOM
2020
CE1
HIS
D
70
6.045
24.214
7.979
1.00
47.53
C
ATOM
2021
NE2
HIS
D
70
4.869
24.094
7.387
1.00
49.18
N
ATOM
2022
CD2
HIS
D
70
5.063
23.940
6.035
1.00
46.48
C
ATOM
2023
C
HIS
D
70
7.467
22.438
2.441
1.00
38.73
C
ATOM
2024
O
HIS
D
70
6.829
22.759
1.422
1.00
39.48
O
ATOM
2025
N
TRP
D
71
8.725
21.994
2.397
1.00
38.01
N
ATOM
2026
CA
TRP
D
71
9.446
21.887
1.121
1.00
36.93
C
ATOM
2027
CB
TRP
D
71
10.920
21.482
1.360
1.00
36.60
C
ATOM
2028
CG
TRP
D
71
11.596
21.051
0.116
1.00
35.32
C
ATOM
2029
CD1
TRP
D
71
12.129
21.868
−0.845
1.00
36.20
C
ATOM
2030
NE1
TRP
D
71
12.666
21.117
−1.863
1.00
33.00
N
ATOM
2031
CE2
TRP
D
71
12.492
19.786
−1.575
1.00
33.99
C
ATOM
2032
CD2
TRP
D
71
11.801
19.706
−0.337
1.00
33.26
C
ATOM
2033
CE3
TRP
D
71
11.486
18.448
0.185
1.00
29.61
C
ATOM
2034
CZ3
TRP
D
71
11.830
17.336
−0.535
1.00
34.23
C
ATOM
2035
CH2
TRP
D
71
12.498
17.450
−1.790
1.00
34.83
C
ATOM
2036
CZ2
TRP
D
71
12.820
18.668
−2.319
1.00
32.77
C
ATOM
2037
C
TRP
D
71
8.754
20.885
0.194
1.00
37.16
C
ATOM
2038
O
TRP
D
71
8.694
21.086
−1.021
1.00
37.02
O
ATOM
2039
N
LEU
D
72
8.255
19.790
0.744
1.00
37.29
N
ATOM
2040
CA
LEU
D
72
7.503
18.834
−0.072
1.00
38.20
C
ATOM
2041
CB
LEU
D
72
6.952
17.721
0.795
1.00
37.67
C
ATOM
2042
CG
LEU
D
72
7.960
16.753
1.405
1.00
38.01
C
ATOM
2043
CD1
LEU
D
72
7.214
15.930
2.418
1.00
36.10
C
ATOM
2044
CD2
LEU
D
72
8.554
15.878
0.336
1.00
37.04
C
ATOM
2045
C
LEU
D
72
6.381
19.501
−0.894
1.00
38.76
C
ATOM
2046
O
LEU
D
72
6.122
19.104
−2.037
1.00
38.00
O
ATOM
2047
N
ARG
D
73
5.789
20.555
−0.332
1.00
39.92
N
ATOM
2048
CA
ARG
D
73
4.608
21.205
−0.903
1.00
41.93
C
ATOM
2049
CB
ARG
D
73
3.477
21.262
0.139
1.00
41.43
C
ATOM
2050
CG
ARG
D
73
3.054
19.908
0.710
1.00
41.64
C
ATOM
2051
CD
ARG
D
73
1.665
20.001
1.435
1.00
42.77
C
ATOM
2052
NE
ARG
D
73
0.577
20.306
0.489
1.00
41.40
N
ATOM
2053
CZ
ARG
D
73
−0.128
21.435
0.432
1.00
41.05
C
ATOM
2054
NH1
ARG
D
73
0.061
22.426
1.297
1.00
38.28
N
ATOM
2055
NH2
ARG
D
73
−1.048
21.575
−0.533
1.00
40.79
N
ATOM
2056
C
ARG
D
73
4.926
22.597
−1.457
1.00
43.33
C
ATOM
2057
O
ARG
D
73
4.018
23.377
−1.768
1.00
44.11
O
ATOM
2058
N
GLY
D
74
6.222
22.914
−1.564
1.00
44.01
N
ATOM
2059
CA
GLY
D
74
6.686
24.181
−2.145
1.00
45.02
C
ATOM
2060
C
GLY
D
74
6.470
25.382
−1.248
1.00
45.92
C
ATOM
2061
O
GLY
D
74
6.309
26.515
−1.713
1.00
46.72
O
ATOM
2062
N
LEU
D
75
6.445
25.149
0.051
1.00
46.34
N
ATOM
2063
CA
LEU
D
75
6.107
26.222
0.997
1.00
47.13
C
ATOM
2064
CB
LEU
D
75
4.934
25.777
1.885
1.00
46.90
C
ATOM
2065
CG
LEU
D
75
3.568
25.669
1.231
1.00
46.99
C
ATOM
2066
CD1
LEU
D
75
2.730
24.757
2.056
1.00
48.19
C
ATOM
2067
CD2
LEU
D
75
2.944
27.049
1.136
1.00
47.54
C
ATOM
2068
C
LEU
D
75
7.309
26.631
1.869
1.00
47.52
C
ATOM
2069
O
LEU
D
75
7.141
27.245
2.939
1.00
48.30
O
ATOM
2070
N
CYS
D
76
8.509
26.251
1.423
1.00
47.15
N
ATOM
2071
CA
CYS
D
76
9.741
26.554
2.151
1.00
47.29
C
ATOM
2072
CB
CYS
D
76
10.341
25.307
2.803
1.00
46.82
C
ATOM
2073
SG
CYS
D
76
11.782
25.664
3.833
1.00
44.67
S
ATOM
2074
C
CYS
D
76
10.736
27.187
1.201
1.00
47.45
C
ATOM
2075
O
CYS
D
76
11.029
26.650
0.125
1.00
47.30
O
ATOM
2076
N
LYS
D
77
11.231
28.342
1.639
1.00
48.56
N
ATOM
2077
CA
LYS
D
77
12.129
29.218
0.883
1.00
49.52
C
ATOM
2078
CB
LYS
D
77
11.691
30.695
1.055
1.00
50.19
C
ATOM
2079
CG
LYS
D
77
10.278
31.028
0.538
1.00
53.97
C
ATOM
2080
CD
LYS
D
77
10.225
30.845
−0.981
1.00
58.79
C
ATOM
2081
CE
LYS
D
77
9.050
29.979
−1.397
1.00
62.13
C
ATOM
2082
NZ
LYS
D
77
9.133
29.643
−2.858
1.00
64.34
N
ATOM
2083
C
LYS
D
77
13.584
29.101
1.377
1.00
48.54
C
ATOM
2084
O
LYS
D
77
14.485
29.711
0.788
1.00
48.99
O
ATOM
2085
N
LYS
D
78
13.787
28.351
2.466
1.00
47.21
N
ATOM
2086
CA
LYS
D
78
15.080
28.269
3.165
1.00
46.17
C
ATOM
2087
CB
LYS
D
78
14.865
27.778
4.588
1.00
45.59
C
ATOM
2088
CG
LYS
D
78
14.052
28.736
5.431
1.00
48.72
C
ATOM
2089
CD
LYS
D
78
13.535
28.042
6.657
1.00
51.08
C
ATOM
2090
CE
LYS
D
78
12.626
28.955
7.426
1.00
54.63
C
ATOM
2091
NZ
LYS
D
78
12.237
28.258
8.680
1.00
57.29
N
ATOM
2092
C
LYS
D
78
16.216
27.465
2.488
1.00
45.04
C
ATOM
2093
O
LYS
D
78
17.366
27.532
2.929
1.00
45.07
O
ATOM
2094
N
GLY
D
79
15.912
26.718
1.432
1.00
43.75
N
ATOM
2095
CA
GLY
D
79
16.935
25.956
0.712
1.00
42.63
C
ATOM
2096
C
GLY
D
79
17.814
25.108
1.629
1.00
41.82
C
ATOM
2097
O
GLY
D
79
17.323
24.490
2.582
1.00
41.57
O
ATOM
2098
N
ASP
D
80
19.118
25.104
1.346
1.00
41.32
N
ATOM
2099
CA
ASP
D
80
20.137
24.381
2.150
1.00
41.34
C
ATOM
2100
CB
ASP
D
80
21.551
24.566
1.548
1.00
40.65
C
ATOM
2101
CG
ASP
D
80
21.723
23.844
0.223
1.00
41.10
C
ATOM
2102
OD1
ASP
D
80
20.833
23.048
−0.171
1.00
41.81
O
ATOM
2103
OD2
ASP
D
80
22.763
24.061
−0.440
1.00
41.86
O
ATOM
2104
C
ASP
D
80
20.153
24.779
3.609
1.00
40.66
C
ATOM
2105
O
ASP
D
80
20.533
23.985
4.474
1.00
40.51
O
ATOM
2106
N
GLN
D
81
19.678
25.988
3.874
1.00
40.84
N
ATOM
2107
CA
GLN
D
81
19.728
26.572
5.205
1.00
40.62
C
ATOM
2108
CB
GLN
D
81
19.909
28.096
5.119
1.00
40.77
C
ATOM
2109
CG
GLN
D
81
21.305
28.536
4.655
1.00
41.97
C
ATOM
2110
CD
GLN
D
81
21.538
28.288
3.171
1.00
43.96
C
ATOM
2111
OE1
GLN
D
81
20.627
28.463
2.370
1.00
44.29
O
ATOM
2112
NE2
GLN
D
81
22.752
27.878
2.797
1.00
40.50
N
ATOM
2113
C
GLN
D
81
18.514
26.200
6.071
1.00
40.22
C
ATOM
2114
O
GLN
D
81
18.448
26.615
7.231
1.00
39.54
O
ATOM
2115
N
CYS
D
82
17.575
25.410
5.526
1.00
39.25
N
ATOM
2116
CA
CYS
D
82
16.459
24.923
6.329
1.00
38.42
C
ATOM
2117
CB
CYS
D
82
15.385
24.223
5.486
1.00
38.37
C
ATOM
2118
SG
CYS
D
82
13.883
23.896
6.491
1.00
38.87
S
ATOM
2119
C
CYS
D
82
16.962
23.975
7.411
1.00
38.75
C
ATOM
2120
O
CYS
D
82
17.970
23.296
7.235
1.00
38.23
O
ATOM
2121
N
GLU
D
83
16.260
23.945
8.534
1.00
38.22
N
ATOM
2122
CA
GLU
D
83
16.586
23.050
9.622
1.00
38.64
C
ATOM
2123
CB
GLU
D
83
15.717
23.407
10.845
1.00
38.85
C
ATOM
2124
CG
GLU
D
83
15.738
22.391
11.960
1.00
39.99
C
ATOM
2125
CD
GLU
D
83
14.765
22.732
13.111
1.00
43.45
C
ATOM
2126
OE1
GLU
D
83
14.146
23.834
13.100
1.00
49.61
O
ATOM
2127
OE2
GLU
D
83
14.624
21.882
14.025
1.00
47.89
O
ATOM
2128
C
GLU
D
83
16.364
21.615
9.174
1.00
36.61
C
ATOM
2129
O
GLU
D
83
16.969
20.663
9.694
1.00
36.20
O
ATOM
2130
N
PHE
D
84
15.448
21.458
8.218
1.00
35.98
N
ATOM
2131
CA
PHE
D
84
14.988
20.138
7.797
1.00
33.86
C
ATOM
2132
CB
PHE
D
84
13.445
20.073
7.860
1.00
34.81
C
ATOM
2133
CG
PHE
D
84
12.908
20.343
9.227
1.00
34.72
C
ATOM
2134
CD1
PHE
D
84
12.327
21.562
9.522
1.00
37.93
C
ATOM
2135
CE1
PHE
D
84
11.841
21.806
10.805
1.00
39.57
C
ATOM
2136
CZ
PHE
D
84
11.981
20.835
11.803
1.00
37.48
C
ATOM
2137
CE2
PHE
D
84
12.557
19.631
11.533
1.00
39.44
C
ATOM
2138
CD2
PHE
D
84
13.043
19.389
10.238
1.00
37.62
C
ATOM
2139
C
PHE
D
84
15.488
19.841
6.394
1.00
32.86
C
ATOM
2140
O
PHE
D
84
15.867
20.728
5.679
1.00
31.87
O
ATOM
2141
N
LEU
D
85
15.452
18.576
6.012
1.00
32.17
N
ATOM
2142
CA
LEU
D
85
16.090
18.146
4.793
1.00
32.87
C
ATOM
2143
CB
LEU
D
85
16.309
16.646
4.887
1.00
32.14
C
ATOM
2144
CG
LEU
D
85
16.987
15.995
3.686
1.00
32.65
C
ATOM
2145
CD1
LEU
D
85
18.475
16.518
3.562
1.00
30.51
C
ATOM
2146
CD2
LEU
D
85
16.905
14.484
3.898
1.00
32.51
C
ATOM
2147
C
LEU
D
85
15.234
18.444
3.563
1.00
34.15
C
ATOM
2148
O
LEU
D
85
14.022
18.140
3.554
1.00
33.04
O
ATOM
2149
N
HIS
D
86
15.865
19.006
2.527
1.00
33.66
N
ATOM
2150
CA
HIS
D
86
15.177
19.238
1.282
1.00
34.81
C
ATOM
2151
CB
HIS
D
86
15.456
20.639
0.786
1.00
34.31
C
ATOM
2152
CG
HIS
D
86
14.760
21.691
1.587
1.00
33.56
C
ATOM
2153
ND1
HIS
D
86
14.431
22.914
1.062
1.00
35.34
N
ATOM
2154
CE1
HIS
D
86
13.867
23.653
1.998
1.00
35.36
C
ATOM
2155
NE2
HIS
D
86
13.761
22.928
3.092
1.00
34.33
N
ATOM
2156
CD2
HIS
D
86
14.323
21.700
2.869
1.00
32.93
C
ATOM
2157
C
HIS
D
86
15.424
18.223
0.195
1.00
35.48
C
ATOM
2158
O
HIS
D
86
15.701
18.615
−0.934
1.00
36.99
O
ATOM
2159
N
GLU
D
87
15.339
16.938
0.533
1.00
36.60
N
ATOM
2160
CA
GLU
D
87
15.300
15.870
−0.461
1.00
38.04
C
ATOM
2161
CB
GLU
D
87
16.656
15.148
−0.598
1.00
38.88
C
ATOM
2162
CG
GLU
D
87
17.818
16.031
−1.075
1.00
41.12
C
ATOM
2163
CD
GLU
D
87
17.624
16.634
−2.476
1.00
45.48
C
ATOM
2164
OE1
GLU
D
87
16.697
16.215
−3.226
1.00
41.76
O
ATOM
2165
OE2
GLU
D
87
18.399
17.568
−2.803
1.00
45.80
O
ATOM
2166
C
GLU
D
87
14.230
14.862
−0.082
1.00
38.87
C
ATOM
2167
O
GLU
D
87
13.856
14.750
1.096
1.00
37.77
O
ATOM
2168
N
TYR
D
88
13.722
14.118
−1.058
1.00
40.40
N
ATOM
2169
CA
TYR
D
88
12.747
13.090
−0.695
1.00
42.60
C
ATOM
2170
CB
TYR
D
88
11.639
12.789
−1.767
1.00
43.58
C
ATOM
2171
CG
TYR
D
88
10.558
11.877
−1.139
1.00
46.74
C
ATOM
2172
CD1
TYR
D
88
9.714
12.348
−0.109
1.00
47.35
C
ATOM
2173
CE1
TYR
D
88
8.769
11.503
0.523
1.00
49.00
C
ATOM
2174
CZ
TYR
D
88
8.663
10.177
0.152
1.00
47.77
C
ATOM
2175
OH
TYR
D
88
7.779
9.314
0.784
1.00
47.83
O
ATOM
2176
CE2
TYR
D
88
9.506
9.679
−0.843
1.00
51.26
C
ATOM
2177
CD2
TYR
D
88
10.460
10.530
−1.482
1.00
49.05
C
ATOM
2178
C
TYR
D
88
13.410
11.825
−0.149
1.00
42.69
C
ATOM
2179
O
TYR
D
88
13.821
10.941
−0.900
1.00
43.66
O
ATOM
2180
N
ASP
D
89
13.461
11.710
1.169
1.00
42.43
N
ATOM
2181
CA
ASP
D
89
13.906
10.477
1.777
1.00
42.60
C
ATOM
2182
CB
ASP
D
89
15.119
10.778
2.648
1.00
42.36
C
ATOM
2183
CG
ASP
D
89
15.771
9.540
3.182
1.00
42.78
C
ATOM
2184
OD1
ASP
D
89
15.168
8.442
3.116
1.00
42.68
O
ATOM
2185
OD2
ASP
D
89
16.914
9.667
3.670
1.00
44.94
O
ATOM
2186
C
ASP
D
89
12.776
9.836
2.595
1.00
43.43
C
ATOM
2187
O
ASP
D
89
12.476
10.292
3.696
1.00
42.72
O
ATOM
2188
N
MET
D
90
12.179
8.762
2.069
1.00
44.28
N
ATOM
2189
CA
MET
D
90
10.995
8.143
2.686
1.00
47.28
C
ATOM
2190
CB
MET
D
90
10.397
7.019
1.805
1.00
46.57
C
ATOM
2191
CG
MET
D
90
11.272
5.745
1.686
1.00
50.99
C
ATOM
2192
SD
MET
D
90
10.600
4.293
0.770
1.00
55.26
S
ATOM
2193
CE
MET
D
90
10.460
4.964
−0.896
1.00
54.61
C
ATOM
2194
C
MET
D
90
11.283
7.639
4.105
1.00
46.07
C
ATOM
2195
O
MET
D
90
10.355
7.302
4.848
1.00
45.61
O
ATOM
2196
N
THR
D
91
12.570
7.594
4.466
1.00
44.61
N
ATOM
2197
CA
THR
D
91
12.987
7.061
5.747
1.00
43.51
C
ATOM
2198
CB
THR
D
91
14.350
6.254
5.648
1.00
44.59
C
ATOM
2199
OG1
THR
D
91
15.463
7.160
5.457
1.00
45.89
O
ATOM
2200
CG2
THR
D
91
14.305
5.201
4.517
1.00
44.25
C
ATOM
2201
C
THR
D
91
13.144
8.164
6.764
1.00
41.77
C
ATOM
2202
O
THR
D
91
13.354
7.894
7.948
1.00
42.02
O
ATOM
2203
N
LYS
D
92
13.073
9.406
6.306
1.00
38.80
N
ATOM
2204
CA
LYS
D
92
13.220
10.539
7.197
1.00
37.66
C
ATOM
2205
CB
LYS
D
92
14.428
11.401
6.773
1.00
37.27
C
ATOM
2206
CG
LYS
D
92
15.767
10.664
6.901
1.00
40.93
C
ATOM
2207
CD
LYS
D
92
16.930
11.547
6.425
1.00
37.83
C
ATOM
2208
CE
LYS
D
92
18.245
10.765
6.528
1.00
45.63
C
ATOM
2209
NZ
LYS
D
92
19.377
11.764
6.464
1.00
44.22
N
ATOM
2210
C
LYS
D
92
11.955
11.412
7.290
1.00
35.80
C
ATOM
2211
O
LYS
D
92
12.035
12.615
7.539
1.00
34.91
O
ATOM
2212
N
MET
D
93
10.792
10.805
7.099
1.00
34.90
N
ATOM
2213
CA
MET
D
93
9.547
11.588
7.032
1.00
33.48
C
ATOM
2214
CB
MET
D
93
8.496
10.843
6.180
1.00
33.76
C
ATOM
2215
CG
MET
D
93
8.850
10.843
4.652
1.00
29.06
C
ATOM
2216
SD
MET
D
93
8.662
12.469
3.962
1.00
28.76
S
ATOM
2217
CE
MET
D
93
6.963
12.472
3.449
1.00
36.37
C
ATOM
2218
C
MET
D
93
9.058
11.939
8.444
1.00
33.59
C
ATOM
2219
O
MET
D
93
9.258
11.123
9.349
1.00
32.16
O
ATOM
2220
N
PRO
D
94
8.462
13.153
8.632
1.00
33.50
N
ATOM
2221
CA
PRO
D
94
7.834
13.556
9.940
1.00
34.10
C
ATOM
2222
CB
PRO
D
94
7.201
14.957
9.670
1.00
32.63
C
ATOM
2223
CG
PRO
D
94
7.882
15.485
8.457
1.00
37.71
C
ATOM
2224
CD
PRO
D
94
8.380
14.248
7.607
1.00
35.59
C
ATOM
2225
C
PRO
D
94
6.729
12.581
10.396
1.00
33.49
C
ATOM
2226
O
PRO
D
94
6.261
11.740
9.592
1.00
32.95
O
ATOM
2227
N
GLU
D
95
6.306
12.700
11.664
1.00
31.40
N
ATOM
2228
CA
GLU
D
95
5.262
11.838
12.153
1.00
30.11
C
ATOM
2229
CB
GLU
D
95
5.248
11.771
13.704
1.00
31.59
C
ATOM
2230
CG
GLU
D
95
4.077
10.906
14.222
1.00
31.29
C
ATOM
2231
CD
GLU
D
95
4.067
10.647
15.747
1.00
35.15
C
ATOM
2232
OE1
GLU
D
95
3.312
9.736
16.195
1.00
42.96
O
ATOM
2233
OE2
GLU
D
95
4.774
11.367
16.469
1.00
42.80
O
ATOM
2234
C
GLU
D
95
3.932
12.424
11.620
1.00
27.97
C
ATOM
2235
O
GLU
D
95
3.754
13.630
11.549
1.00
26.66
O
ATOM
2236
N
CYS
D
96
3.012
11.552
11.271
1.00
27.21
N
ATOM
2237
CA
CYS
D
96
1.677
11.980
10.816
1.00
26.91
C
ATOM
2238
CB
CYS
D
96
0.972
10.808
10.196
1.00
25.79
C
ATOM
2239
SG
CYS
D
96
−0.756
11.121
9.525
1.00
25.47
S
ATOM
2240
C
CYS
D
96
0.833
12.538
11.964
1.00
27.38
C
ATOM
2241
O
CYS
D
96
0.514
11.837
12.909
1.00
27.92
O
ATOM
2242
N
TYR
D
97
0.452
13.801
11.856
1.00
27.76
N
ATOM
2243
CA
TYR
D
97
−0.365
14.433
12.897
1.00
27.92
C
ATOM
2244
CB
TYR
D
97
−0.652
15.878
12.528
1.00
28.47
C
ATOM
2245
CG
TYR
D
97
−1.354
16.646
13.643
1.00
29.52
C
ATOM
2246
CD1
TYR
D
97
−0.612
17.386
14.560
1.00
30.25
C
ATOM
2247
CE1
TYR
D
97
−1.252
18.093
15.628
1.00
32.82
C
ATOM
2248
CZ
TYR
D
97
−2.655
18.015
15.752
1.00
30.54
C
ATOM
2249
OH
TYR
D
97
−3.281
18.703
16.791
1.00
30.45
O
ATOM
2250
CE2
TYR
D
97
−3.416
17.260
14.837
1.00
29.38
C
ATOM
2251
CD2
TYR
D
97
−2.766
16.571
13.800
1.00
29.06
C
ATOM
2252
C
TYR
D
97
−1.658
13.672
13.141
1.00
28.09
C
ATOM
2253
O
TYR
D
97
−2.045
13.435
14.298
1.00
27.25
O
ATOM
2254
N
PHE
D
98
−2.318
13.251
12.054
1.00
28.03
N
ATOM
2255
CA
PHE
D
98
−3.631
12.613
12.195
1.00
26.18
C
ATOM
2256
CB
PHE
D
98
−4.407
12.608
10.863
1.00
27.78
C
ATOM
2257
CG
PHE
D
98
−4.754
14.003
10.412
1.00
25.25
C
ATOM
2258
CD1
PHE
D
98
−5.815
14.669
10.990
1.00
25.95
C
ATOM
2259
CE1
PHE
D
98
−6.092
15.991
10.625
1.00
25.50
C
ATOM
2260
CZ
PHE
D
98
−5.302
16.649
9.701
1.00
28.69
C
ATOM
2261
CE2
PHE
D
98
−4.223
16.002
9.144
1.00
31.29
C
ATOM
2262
CD2
PHE
D
98
−3.963
14.666
9.492
1.00
27.25
C
ATOM
2263
C
PHE
D
98
−3.515
11.238
12.812
1.00
28.26
C
ATOM
2264
O
PHE
D
98
−4.313
10.893
13.689
1.00
26.63
O
ATOM
2265
N
TYR
D
99
−2.538
10.431
12.375
1.00
28.21
N
ATOM
2266
CA
TYR
D
99
−2.406
9.132
13.024
1.00
30.03
C
ATOM
2267
CB
TYR
D
99
−1.371
8.282
12.328
1.00
29.69
C
ATOM
2268
CG
TYR
D
99
−1.522
6.820
12.659
1.00
31.63
C
ATOM
2269
CD1
TYR
D
99
−2.409
6.015
11.954
1.00
31.51
C
ATOM
2270
CE1
TYR
D
99
−2.547
4.671
12.258
1.00
31.48
C
ATOM
2271
CZ
TYR
D
99
−1.802
4.118
13.295
1.00
34.31
C
ATOM
2272
OH
TYR
D
99
−1.944
2.761
13.594
1.00
35.60
O
ATOM
2273
CE2
TYR
D
99
−0.911
4.897
14.014
1.00
34.34
C
ATOM
2274
CD2
TYR
D
99
−0.772
6.239
13.706
1.00
33.06
C
ATOM
2275
C
TYR
D
99
−2.050
9.285
14.524
1.00
30.74
C
ATOM
2276
O
TYR
D
99
−2.528
8.521
15.362
1.00
31.10
O
ATOM
2277
N
SER
D
100
−1.252
10.292
14.843
1.00
31.22
N
ATOM
2278
CA
SER
D
100
−0.808
10.499
16.231
1.00
33.97
C
ATOM
2279
CB
SER
D
100
0.374
11.452
16.281
1.00
33.74
C
ATOM
2280
OG
SER
D
100
0.531
11.965
17.613
1.00
40.80
O
ATOM
2281
C
SER
D
100
−1.937
11.009
17.142
1.00
33.35
C
ATOM
2282
O
SER
D
100
−2.116
10.476
18.259
1.00
34.24
O
ATOM
2283
N
LYS
D
101
−2.669
12.036
16.694
1.00
32.17
N
ATOM
2284
CA
LYS
D
101
−3.748
12.598
17.513
1.00
32.18
C
ATOM
2285
CB
LYS
D
101
−4.019
14.090
17.233
1.00
31.57
C
ATOM
2286
CG
LYS
D
101
−2.787
14.947
17.229
1.00
35.32
C
ATOM
2287
CD
LYS
D
101
−2.122
15.074
18.568
1.00
41.14
C
ATOM
2288
CE
LYS
D
101
−0.778
15.787
18.385
1.00
45.47
C
ATOM
2289
NZ
LYS
D
101
0.071
15.692
19.614
1.00
49.42
N
ATOM
2290
C
LYS
D
101
−5.043
11.822
17.475
1.00
32.87
C
ATOM
2291
O
LYS
D
101
−5.813
11.880
18.448
1.00
32.25
O
ATOM
2292
N
PHE
D
102
−5.303
11.104
16.366
1.00
32.74
N
ATOM
2293
CA
PHE
D
102
−6.603
10.506
16.130
1.00
31.60
C
ATOM
2294
CB
PHE
D
102
−7.279
11.089
14.871
1.00
31.91
C
ATOM
2295
CG
PHE
D
102
−7.714
12.529
15.022
1.00
29.94
C
ATOM
2296
CD1
PHE
D
102
−9.004
12.848
15.414
1.00
29.78
C
ATOM
2297
CE1
PHE
D
102
−9.402
14.211
15.537
1.00
24.97
C
ATOM
2298
CZ
PHE
D
102
−8.488
15.235
15.305
1.00
30.76
C
ATOM
2299
CE2
PHE
D
102
−7.204
14.894
14.901
1.00
31.66
C
ATOM
2300
CD2
PHE
D
102
−6.840
13.566
14.763
1.00
29.03
C
ATOM
2301
C
PHE
D
102
−6.491
9.005
16.040
1.00
32.14
C
ATOM
2302
O
PHE
D
102
−7.504
8.304
16.084
1.00
32.25
O
ATOM
2303
N
GLY
D
103
−5.275
8.480
15.911
1.00
31.31
N
ATOM
2304
CA
GLY
D
103
−5.174
7.038
15.785
1.00
31.79
C
ATOM
2305
C
GLY
D
103
−5.567
6.419
14.444
1.00
31.97
C
ATOM
2306
O
GLY
D
103
−5.626
5.206
14.333
1.00
32.46
O
ATOM
2307
N
GLU
D
104
−5.772
7.254
13.424
1.00
31.27
N
ATOM
2308
CA
GLU
D
104
−6.165
6.798
12.103
1.00
32.35
C
ATOM
2309
CB
GLU
D
104
−7.700
6.597
12.055
1.00
31.98
C
ATOM
2310
CG
GLU
D
104
−8.414
7.801
12.597
1.00
37.23
C
ATOM
2311
CD
GLU
D
104
−9.943
7.678
12.652
1.00
39.72
C
ATOM
2312
OE1
GLU
D
104
−10.592
8.690
13.160
1.00
49.09
O
ATOM
2313
OE2
GLU
D
104
−10.461
6.616
12.183
1.00
47.00
O
ATOM
2314
C
GLU
D
104
−5.777
7.887
11.094
1.00
28.30
C
ATOM
2315
O
GLU
D
104
−5.610
9.058
11.457
1.00
27.32
O
ATOM
2316
N
CYS
D
105
−5.711
7.505
9.823
1.00
26.03
N
ATOM
2317
CA
CYS
D
105
−5.317
8.438
8.770
1.00
24.64
C
ATOM
2318
CB
CYS
D
105
−3.794
8.380
8.639
1.00
24.89
C
ATOM
2319
SG
CYS
D
105
−3.126
9.266
7.198
1.00
24.05
S
ATOM
2320
C
CYS
D
105
−5.989
7.928
7.501
1.00
25.33
C
ATOM
2321
O
CYS
D
105
−6.010
6.721
7.249
1.00
24.40
O
ATOM
2322
N
SER
D
106
−6.619
8.836
6.741
1.00
25.56
N
ATOM
2323
CA
SER
D
106
−7.389
8.422
5.548
1.00
26.47
C
ATOM
2324
CB
SER
D
106
−8.516
9.453
5.249
1.00
26.24
C
ATOM
2325
OG
SER
D
106
−9.360
9.627
6.387
1.00
28.23
O
ATOM
2326
C
SER
D
106
−6.556
8.272
4.293
1.00
25.71
C
ATOM
2327
O
SER
D
106
−7.097
7.880
3.284
1.00
25.71
O
ATOM
2328
N
ASN
D
107
−5.249
8.580
4.324
1.00
26.46
N
ATOM
2329
CA
ASN
D
107
−4.446
8.453
3.098
1.00
25.74
C
ATOM
2330
CB
ASN
D
107
−3.369
9.531
3.066
1.00
26.14
C
ATOM
2331
CG
ASN
D
107
−2.628
9.608
1.732
1.00
26.49
C
ATOM
2332
OD1
ASN
D
107
−2.882
8.825
0.829
1.00
26.10
O
ATOM
2333
ND2
ASN
D
107
−1.747
10.610
1.599
1.00
25.07
N
ATOM
2334
C
ASN
D
107
−3.799
7.076
2.986
1.00
26.04
C
ATOM
2335
O
ASN
D
107
−2.829
6.795
3.679
1.00
24.98
O
ATOM
2336
N
LYS
D
108
−4.287
6.235
2.078
1.00
26.11
N
ATOM
2337
CA
LYS
D
108
−3.702
4.897
1.874
1.00
27.13
C
ATOM
2338
CB
LYS
D
108
−4.374
4.196
0.702
1.00
27.98
C
ATOM
2339
CG
LYS
D
108
−5.821
3.823
0.946
1.00
28.66
C
ATOM
2340
CD
LYS
D
108
−6.383
2.992
−0.222
1.00
28.13
C
ATOM
2341
CE
LYS
D
108
−7.909
3.041
−0.137
1.00
29.83
C
ATOM
2342
NZ
LYS
D
108
−8.548
2.711
−1.468
1.00
33.21
N
ATOM
2343
C
LYS
D
108
−2.236
5.019
1.559
1.00
28.60
C
ATOM
2344
O
LYS
D
108
−1.474
4.091
1.797
1.00
28.74
O
ATOM
2345
N
GLU
D
109
−1.833
6.181
1.040
1.00
28.07
N
ATOM
2346
CA
GLU
D
109
−0.454
6.365
0.587
1.00
29.49
C
ATOM
2347
CB
GLU
D
109
−0.418
6.922
−0.872
1.00
29.49
C
ATOM
2348
CG
GLU
D
109
−0.531
5.937
−2.016
1.00
33.84
C
ATOM
2349
CD
GLU
D
109
−1.877
5.272
−2.118
1.00
38.05
C
ATOM
2350
OE1
GLU
D
109
−2.892
5.951
−2.409
1.00
37.86
O
ATOM
2351
OE2
GLU
D
109
−1.903
4.025
−1.918
1.00
43.82
O
ATOM
2352
C
GLU
D
109
0.234
7.360
1.531
1.00
27.85
C
ATOM
2353
O
GLU
D
109
1.170
8.038
1.126
1.00
27.90
O
ATOM
2354
N
CYS
D
110
−0.224
7.468
2.794
1.00
27.24
N
ATOM
2355
CA
CYS
D
110
0.349
8.464
3.668
1.00
26.45
C
ATOM
2356
CB
CYS
D
110
−0.217
8.424
5.110
1.00
26.19
C
ATOM
2357
SG
CYS
D
110
0.473
9.819
6.015
1.00
26.60
S
ATOM
2358
C
CYS
D
110
1.861
8.236
3.757
1.00
26.83
C
ATOM
2359
O
CYS
D
110
2.306
7.136
4.093
1.00
27.21
O
ATOM
2360
N
PRO
D
111
2.644
9.264
3.464
1.00
28.24
N
ATOM
2361
CA
PRO
D
111
4.100
9.026
3.588
1.00
29.52
C
ATOM
2362
CB
PRO
D
111
4.693
9.997
2.571
1.00
29.24
C
ATOM
2363
CG
PRO
D
111
3.697
11.231
2.593
1.00
29.52
C
ATOM
2364
CD
PRO
D
111
2.314
10.617
2.940
1.00
28.03
C
ATOM
2365
C
PRO
D
111
4.652
9.291
5.006
1.00
30.98
C
ATOM
2366
O
PRO
D
111
5.844
9.085
5.254
1.00
30.98
O
ATOM
2367
N
PHE
D
112
3.804
9.736
5.928
1.00
30.89
N
ATOM
2368
CA
PHE
D
112
4.269
10.140
7.250
1.00
31.40
C
ATOM
2369
CB
PHE
D
112
3.488
11.400
7.720
1.00
30.20
C
ATOM
2370
CG
PHE
D
112
3.666
12.592
6.808
1.00
31.21
C
ATOM
2371
CD1
PHE
D
112
4.830
13.347
6.840
1.00
29.10
C
ATOM
2372
CE1
PHE
D
112
4.997
14.422
5.991
1.00
29.55
C
ATOM
2373
CZ
PHE
D
112
3.956
14.776
5.080
1.00
30.53
C
ATOM
2374
CE2
PHE
D
112
2.787
14.019
5.060
1.00
29.65
C
ATOM
2375
CD2
PHE
D
112
2.657
12.959
5.902
1.00
29.41
C
ATOM
2376
C
PHE
D
112
4.207
8.961
8.248
1.00
32.22
C
ATOM
2377
O
PHE
D
112
3.457
7.988
8.060
1.00
31.82
O
ATOM
2378
N
LEU
D
113
5.006
9.029
9.317
1.00
32.63
N
ATOM
2379
CA
LEU
D
113
5.022
7.932
10.298
1.00
33.39
C
ATOM
2380
CB
LEU
D
113
6.094
8.155
11.371
1.00
33.96
C
ATOM
2381
CG
LEU
D
113
7.531
8.394
10.944
1.00
36.30
C
ATOM
2382
CD1
LEU
D
113
8.354
8.768
12.166
1.00
38.73
C
ATOM
2383
CD2
LEU
D
113
8.092
7.138
10.288
1.00
40.51
C
ATOM
2384
C
LEU
D
113
3.682
7.730
11.012
1.00
33.17
C
ATOM
2385
O
LEU
D
113
3.125
8.664
11.575
1.00
32.95
O
ATOM
2386
N
HIS
D
114
3.226
6.489
11.016
1.00
33.23
N
ATOM
2387
CA
HIS
D
114
2.100
6.069
11.799
1.00
35.48
C
ATOM
2388
CB
HIS
D
114
1.117
5.267
10.947
1.00
34.35
C
ATOM
2389
CG
HIS
D
114
0.415
6.058
9.871
1.00
30.91
C
ATOM
2390
ND1
HIS
D
114
−0.475
5.460
9.007
1.00
30.62
N
ATOM
2391
CE1
HIS
D
114
−0.961
6.359
8.166
1.00
29.38
C
ATOM
2392
NE2
HIS
D
114
−0.466
7.543
8.486
1.00
21.78
N
ATOM
2393
CD2
HIS
D
114
0.420
7.374
9.546
1.00
25.39
C
ATOM
2394
C
HIS
D
114
2.577
5.228
13.001
1.00
37.49
C
ATOM
2395
O
HIS
D
114
2.769
4.011
12.893
1.00
38.30
O
ATOM
2396
N
ILE
D
115
2.744
5.897
14.124
1.00
40.28
N
ATOM
2397
CA
ILE
D
115
3.278
5.292
15.358
1.00
44.28
C
ATOM
2398
CB
ILE
D
115
4.306
6.217
16.026
1.00
43.85
C
ATOM
2399
CG1
ILE
D
115
5.492
6.454
15.092
1.00
43.41
C
ATOM
2400
CD1
ILE
D
115
6.188
7.704
15.411
1.00
43.55
C
ATOM
2401
CG2
ILE
D
115
4.798
5.626
17.367
1.00
45.91
C
ATOM
2402
C
ILE
D
115
2.145
5.013
16.347
1.00
46.74
C
ATOM
2403
O
ILE
D
115
1.410
5.930
16.739
1.00
45.72
O
ATOM
2404
N
ASP
D
116
2.009
3.739
16.714
1.00
50.52
N
ATOM
2405
CA
ASP
D
116
0.967
3.299
17.636
1.00
54.53
C
ATOM
2406
CB
ASP
D
116
0.748
1.815
17.497
1.00
54.79
C
ATOM
2407
CG
ASP
D
116
−0.004
1.487
16.252
1.00
57.65
C
ATOM
2408
OD1
ASP
D
116
−0.920
2.284
15.908
1.00
58.31
O
ATOM
2409
OD2
ASP
D
116
0.332
0.459
15.605
1.00
60.82
O
ATOM
2410
C
ASP
D
116
1.257
3.653
19.082
1.00
57.26
C
ATOM
2411
O
ASP
D
116
2.430
3.687
19.507
1.00
57.07
O
ATOM
2412
N
PRO
D
117
0.187
3.944
19.844
1.00
59.98
N
ATOM
2413
CA
PRO
D
117
0.354
4.429
21.206
1.00
62.24
C
ATOM
2414
CB
PRO
D
117
−1.063
4.434
21.747
1.00
62.12
C
ATOM
2415
CG
PRO
D
117
−1.913
4.600
20.533
1.00
61.61
C
ATOM
2416
CD
PRO
D
117
−1.233
3.827
19.468
1.00
60.37
C
ATOM
2417
C
PRO
D
117
1.253
3.461
21.965
1.00
64.67
C
ATOM
2418
O
PRO
D
117
1.000
2.237
21.993
1.00
64.83
O
ATOM
2419
N
GLU
D
118
2.326
4.029
22.514
1.00
67.27
N
ATOM
2420
CA
GLU
D
118
3.477
3.280
23.006
1.00
69.59
C
ATOM
2421
CB
GLU
D
118
4.684
4.230
23.201
1.00
70.33
C
ATOM
2422
CG
GLU
D
118
5.298
4.836
21.899
1.00
73.39
C
ATOM
2423
CD
GLU
D
118
4.568
6.103
21.334
1.00
76.34
C
ATOM
2424
OE1
GLU
D
118
5.246
7.142
21.133
1.00
78.16
O
ATOM
2425
OE2
GLU
D
118
3.342
6.068
21.065
1.00
76.31
O
ATOM
2426
C
GLU
D
118
3.091
2.594
24.317
1.00
70.03
C
ATOM
2427
O
GLU
D
118
2.772
1.396
24.331
1.00
70.42
O
ATOM
2428
OXT
GLU
D
118
3.057
3.230
25.381
1.00
70.37
O
ATOM
2429
ZN
ZN
D
502
−0.941
9.474
7.886
1.00
26.96
ZN
ATOM
2430
ZN
ZN
D
501
12.470
23.684
4.582
1.00
38.67
ZN
ATOM
2431
N
HIS
E
58
−45.599
5.932
−6.806
1.00
42.25
N
ATOM
2432
CA
HIS
E
58
−44.990
6.748
−5.741
1.00
41.89
C
ATOM
2433
CB
HIS
E
58
−43.463
6.785
−5.831
1.00
44.50
C
ATOM
2434
CG
HIS
E
58
−42.795
6.886
−4.479
1.00
50.77
C
ATOM
2435
ND1
HIS
E
58
−43.456
7.346
−3.347
1.00
54.95
N
ATOM
2436
CE1
HIS
E
58
−42.629
7.341
−2.319
1.00
56.42
C
ATOM
2437
NE2
HIS
E
58
−41.448
6.908
−2.737
1.00
57.08
N
ATOM
2438
CD2
HIS
E
58
−41.527
6.607
−4.081
1.00
54.69
C
ATOM
2439
C
HIS
E
58
−45.544
8.155
−5.678
1.00
39.42
C
ATOM
2440
O
HIS
E
58
−46.314
8.545
−6.529
1.00
39.21
O
ATOM
2441
N
HIS
E
59
−45.137
8.891
−4.639
1.00
36.77
N
ATOM
2442
CA
HIS
E
59
−45.638
10.226
−4.323
1.00
34.79
C
ATOM
2443
CB
HIS
E
59
−45.422
10.533
−2.828
1.00
34.59
C
ATOM
2444
CG
HIS
E
59
−46.395
9.818
−1.940
1.00
33.03
C
ATOM
2445
ND1
HIS
E
59
−47.619
10.358
−1.596
1.00
32.36
N
ATOM
2446
CE1
HIS
E
59
−48.284
9.494
−0.853
1.00
31.07
C
ATOM
2447
NE2
HIS
E
59
−47.546
8.412
−0.712
1.00
33.32
N
ATOM
2448
CD2
HIS
E
59
−46.366
8.577
−1.404
1.00
33.19
C
ATOM
2449
C
HIS
E
59
−45.044
11.294
−5.192
1.00
33.88
C
ATOM
2450
O
HIS
E
59
−45.621
12.347
−5.359
1.00
34.21
O
ATOM
2451
N
MET
E
60
−43.868
11.030
−5.751
1.00
33.64
N
ATOM
2452
CA
MET
E
60
−43.150
12.064
−6.456
1.00
32.83
C
ATOM
2453
CB
MET
E
60
−41.660
12.062
−6.014
1.00
33.04
C
ATOM
2454
CG
MET
E
60
−41.453
12.437
−4.513
1.00
31.91
C
ATOM
2455
SD
MET
E
60
−41.776
14.194
−4.217
1.00
32.73
S
ATOM
2456
CE
MET
E
60
−40.473
15.014
−5.195
1.00
37.28
C
ATOM
2457
C
MET
E
60
−43.287
11.794
−7.946
1.00
32.82
C
ATOM
2458
O
MET
E
60
−43.281
10.640
−8.378
1.00
31.69
O
ATOM
2459
N
SER
E
61
−43.409
12.856
−8.720
1.00
34.88
N
ATOM
2460
CA
SER
E
61
−43.525
12.717
−10.180
1.00
36.77
C
ATOM
2461
CB
SER
E
61
−43.851
14.048
−10.771
1.00
36.98
C
ATOM
2462
OG
SER
E
61
−42.777
14.923
−10.515
1.00
36.64
O
ATOM
2463
C
SER
E
61
−42.240
12.186
−10.826
1.00
38.65
C
ATOM
2464
O
SER
E
61
−42.276
11.508
−11.861
1.00
38.84
O
ATOM
2465
N
GLY
E
62
−41.109
12.548
−10.238
1.00
38.90
N
ATOM
2466
CA
GLY
E
62
−39.821
11.937
−10.565
1.00
42.02
C
ATOM
2467
C
GLY
E
62
−38.915
12.104
−9.370
1.00
42.64
C
ATOM
2468
O
GLY
E
62
−39.227
12.872
−8.468
1.00
42.24
O
ATOM
2469
N
GLU
E
63
−37.796
11.393
−9.347
1.00
45.02
N
ATOM
2470
CA
GLU
E
63
−36.847
11.545
−8.225
1.00
47.21
C
ATOM
2471
CB
GLU
E
63
−36.811
10.301
−7.315
1.00
47.94
C
ATOM
2472
CG
GLU
E
63
−36.103
9.079
−7.946
1.00
50.89
C
ATOM
2473
CD
GLU
E
63
−35.983
7.892
−7.000
1.00
52.10
C
ATOM
2474
OE1
GLU
E
63
−36.013
8.100
−5.750
1.00
59.78
O
ATOM
2475
OE2
GLU
E
63
−35.856
6.753
−7.508
1.00
58.02
O
ATOM
2476
C
GLU
E
63
−35.450
11.851
−8.749
1.00
46.14
C
ATOM
2477
O
GLU
E
63
−35.088
11.464
−9.878
1.00
46.17
O
ATOM
2478
N
LYS
E
64
−34.683
12.571
−7.939
1.00
44.27
N
ATOM
2479
CA
LYS
E
64
−33.270
12.750
−8.212
1.00
42.93
C
ATOM
2480
CB
LYS
E
64
−32.739
13.869
−7.367
1.00
41.82
C
ATOM
2481
CG
LYS
E
64
−33.343
15.218
−7.693
1.00
41.03
C
ATOM
2482
CD
LYS
E
64
−33.057
16.133
−6.512
1.00
41.77
C
ATOM
2483
CE
LYS
E
64
−33.368
17.576
−6.788
1.00
41.00
C
ATOM
2484
NZ
LYS
E
64
−32.771
18.415
−5.702
1.00
40.32
N
ATOM
2485
C
LYS
E
64
−32.560
11.436
−7.918
1.00
42.50
C
ATOM
2486
O
LYS
E
64
−33.026
10.610
−7.135
1.00
44.38
O
ATOM
2487
N
THR
E
65
−31.441
11.193
−8.562
1.00
42.38
N
ATOM
2488
CA
THR
E
65
−30.831
9.888
−8.402
1.00
41.77
C
ATOM
2489
CB
THR
E
65
−30.720
9.186
−9.760
1.00
42.28
C
ATOM
2490
OG1
THR
E
65
−30.159
10.128
−10.693
1.00
41.94
O
ATOM
2491
CG2
THR
E
65
−32.135
8.713
−10.241
1.00
45.27
C
ATOM
2492
C
THR
E
65
−29.423
9.995
−7.862
1.00
40.59
C
ATOM
2493
O
THR
E
65
−28.849
8.977
−7.475
1.00
40.78
O
ATOM
2494
N
VAL
E
66
−28.842
11.193
−7.905
1.00
38.83
N
ATOM
2495
CA
VAL
E
66
−27.426
11.331
−7.492
1.00
37.55
C
ATOM
2496
CB
VAL
E
66
−26.459
11.437
−8.729
1.00
38.38
C
ATOM
2497
CG1
VAL
E
66
−25.006
11.254
−8.300
1.00
37.81
C
ATOM
2498
CG2
VAL
E
66
−26.794
10.360
−9.780
1.00
38.40
C
ATOM
2499
C
VAL
E
66
−27.227
12.484
−6.511
1.00
35.67
C
ATOM
2500
O
VAL
E
66
−27.741
13.564
−6.731
1.00
35.07
O
ATOM
2501
N
VAL
E
67
−26.471
12.247
−5.427
1.00
35.49
N
ATOM
2502
CA
VAL
E
67
−26.180
13.321
−4.440
1.00
33.32
C
ATOM
2503
CB
VAL
E
67
−25.455
12.741
−3.186
1.00
34.57
C
ATOM
2504
CG1
VAL
E
67
−25.038
13.845
−2.204
1.00
32.91
C
ATOM
2505
CG2
VAL
E
67
−26.283
11.653
−2.507
1.00
34.32
C
ATOM
2506
C
VAL
E
67
−25.326
14.407
−5.084
1.00
33.24
C
ATOM
2507
O
VAL
E
67
−24.399
14.102
−5.828
1.00
33.82
O
ATOM
2508
N
CYS
E
68
−25.604
15.669
−4.811
1.00
31.69
N
ATOM
2509
CA
CYS
E
68
−24.799
16.744
−5.313
1.00
31.28
C
ATOM
2510
CB
CYS
E
68
−25.538
18.035
−5.075
1.00
29.96
C
ATOM
2511
SG
CYS
E
68
−24.739
19.465
−5.730
1.00
33.39
S
ATOM
2512
C
CYS
E
68
−23.381
16.862
−4.647
1.00
31.68
C
ATOM
2513
O
CYS
E
68
−23.271
17.214
−3.467
1.00
28.47
O
ATOM
2514
N
LYS
E
69
−22.325
16.598
−5.431
1.00
31.61
N
ATOM
2515
CA
LYS
E
69
−20.908
16.763
−5.017
1.00
32.83
C
ATOM
2516
CB
LYS
E
69
−20.027
16.837
−6.279
1.00
33.94
C
ATOM
2517
CG
LYS
E
69
−19.380
15.596
−6.682
1.00
36.27
C
ATOM
2518
CD
LYS
E
69
−18.340
15.955
−7.751
1.00
36.61
C
ATOM
2519
CE
LYS
E
69
−16.997
16.551
−7.151
1.00
35.02
C
ATOM
2520
NZ
LYS
E
69
−16.668
17.768
−7.999
1.00
34.32
N
ATOM
2521
C
LYS
E
69
−20.618
18.068
−4.349
1.00
32.43
C
ATOM
2522
O
LYS
E
69
−19.978
18.119
−3.327
1.00
33.76
O
ATOM
2523
N
HIS
E
70
−20.993
19.132
−5.029
1.00
32.65
N
ATOM
2524
CA
HIS
E
70
−20.764
20.507
−4.616
1.00
34.13
C
ATOM
2525
CB
HIS
E
70
−21.208
21.475
−5.716
1.00
35.61
C
ATOM
2526
CG
HIS
E
70
−20.401
21.362
−6.974
1.00
41.83
C
ATOM
2527
ND1
HIS
E
70
−20.975
21.215
−8.219
1.00
44.87
N
ATOM
2528
CE1
HIS
E
70
−20.021
21.107
−9.131
1.00
46.74
C
ATOM
2529
NE2
HIS
E
70
−18.850
21.169
−8.521
1.00
46.66
N
ATOM
2530
CD2
HIS
E
70
−19.057
21.348
−7.173
1.00
45.07
C
ATOM
2531
C
HIS
E
70
−21.499
20.875
−3.375
1.00
33.85
C
ATOM
2532
O
HIS
E
70
−20.965
21.612
−2.540
1.00
32.81
O
ATOM
2533
N
TRP
E
71
−22.735
20.382
−3.234
1.00
32.72
N
ATOM
2534
CA
TRP
E
71
−23.473
20.633
−1.999
1.00
31.55
C
ATOM
2535
CB
TRP
E
71
−24.898
20.093
−2.128
1.00
31.78
C
ATOM
2536
CG
TRP
E
71
−25.618
20.081
−0.863
1.00
30.88
C
ATOM
2537
CD1
TRP
E
71
−26.208
21.145
−0.255
1.00
32.24
C
ATOM
2538
NE1
TRP
E
71
−26.752
20.766
0.939
1.00
30.42
N
ATOM
2539
CE2
TRP
E
71
−26.545
19.423
1.119
1.00
31.60
C
ATOM
2540
CD2
TRP
E
71
−25.810
18.959
0.001
1.00
31.97
C
ATOM
2541
CE3
TRP
E
71
−25.453
17.599
−0.064
1.00
29.83
C
ATOM
2542
CZ3
TRP
E
71
−25.828
16.755
0.982
1.00
31.73
C
ATOM
2543
CH2
TRP
E
71
−26.576
17.246
2.082
1.00
31.68
C
ATOM
2544
CZ2
TRP
E
71
−26.932
18.579
2.164
1.00
33.50
C
ATOM
2545
C
TRP
E
71
−22.779
19.988
−0.793
1.00
31.55
C
ATOM
2546
O
TRP
E
71
−22.696
20.588
0.273
1.00
31.49
O
ATOM
2547
N
LEU
E
72
−22.324
18.753
−0.940
1.00
31.49
N
ATOM
2548
CA
LEU
E
72
−21.521
18.104
0.095
1.00
33.29
C
ATOM
2549
CB
LEU
E
72
−20.882
16.817
−0.408
1.00
32.05
C
ATOM
2550
CG
LEU
E
72
−21.709
15.628
−0.834
1.00
33.40
C
ATOM
2551
CD1
LEU
E
72
−20.740
14.576
−1.311
1.00
33.05
C
ATOM
2552
CD2
LEU
E
72
−22.533
15.074
0.324
1.00
34.38
C
ATOM
2553
C
LEU
E
72
−20.421
18.995
0.666
1.00
35.07
C
ATOM
2554
O
LEU
E
72
−20.179
18.977
1.889
1.00
34.12
O
ATOM
2555
N
ARG
E
73
−19.811
19.800
−0.211
1.00
36.81
N
ATOM
2556
CA
ARG
E
73
−18.657
20.617
0.109
1.00
40.54
C
ATOM
2557
CB
ARG
E
73
−17.582
20.487
−0.995
1.00
40.08
C
ATOM
2558
CG
ARG
E
73
−17.188
19.023
−1.253
1.00
38.53
C
ATOM
2559
CD
ARG
E
73
−15.766
18.806
−1.829
1.00
42.91
C
ATOM
2560
NE
ARG
E
73
−14.721
19.373
−0.957
1.00
44.71
N
ATOM
2561
CZ
ARG
E
73
−13.988
20.441
−1.248
1.00
41.53
C
ATOM
2562
NH1
ARG
E
73
−14.110
21.056
−2.418
1.00
38.99
N
ATOM
2563
NH2
ARG
E
73
−13.095
20.874
−0.366
1.00
39.88
N
ATOM
2564
C
ARG
E
73
−19.038
22.074
0.384
1.00
42.77
C
ATOM
2565
O
ARG
E
73
−18.175
22.881
0.710
1.00
44.16
O
ATOM
2566
N
GLY
E
74
−20.336
22.386
0.298
1.00
44.23
N
ATOM
2567
CA
GLY
E
74
−20.858
23.741
0.583
1.00
46.05
C
ATOM
2568
C
GLY
E
74
−20.728
24.678
−0.610
1.00
46.86
C
ATOM
2569
O
GLY
E
74
−20.793
25.910
−0.460
1.00
48.02
O
ATOM
2570
N
LEU
E
75
−20.532
24.104
−1.791
1.00
47.48
N
ATOM
2571
CA
LEU
E
75
−20.302
24.871
−3.020
1.00
48.84
C
ATOM
2572
CB
LEU
E
75
−19.129
24.266
−3.816
1.00
49.51
C
ATOM
2573
CG
LEU
E
75
−17.738
24.086
−3.189
1.00
50.58
C
ATOM
2574
CD1
LEU
E
75
−16.902
23.169
−4.073
1.00
50.57
C
ATOM
2575
CD2
LEU
E
75
−17.066
25.434
−2.994
1.00
50.81
C
ATOM
2576
C
LEU
E
75
−21.498
24.943
−3.983
1.00
49.52
C
ATOM
2577
O
LEU
E
75
−21.321
25.345
−5.153
1.00
50.54
O
ATOM
2578
N
CYS
E
76
−22.682
24.497
−3.561
1.00
48.50
N
ATOM
2579
CA
CYS
E
76
−23.841
24.558
−4.460
1.00
49.32
C
ATOM
2580
CB
CYS
E
76
−24.746
23.332
−4.338
1.00
49.22
C
ATOM
2581
SG
CYS
E
76
−25.966
23.095
−5.719
1.00
45.68
S
ATOM
2582
C
CYS
E
76
−24.616
25.803
−4.123
1.00
50.25
C
ATOM
2583
O
CYS
E
76
−24.951
26.040
−2.956
1.00
50.15
O
ATOM
2584
N
LYS
E
77
−24.885
26.608
−5.145
1.00
51.41
N
ATOM
2585
CA
LYS
E
77
−25.629
27.849
−4.945
1.00
52.98
C
ATOM
2586
CB
LYS
E
77
−24.868
29.022
−5.590
1.00
54.17
C
ATOM
2587
CG
LYS
E
77
−23.520
29.356
−4.910
1.00
55.63
C
ATOM
2588
CD
LYS
E
77
−23.643
29.529
−3.369
1.00
59.35
C
ATOM
2589
CE
LYS
E
77
−22.265
29.528
−2.689
1.00
60.06
C
ATOM
2590
NZ
LYS
E
77
−22.296
28.836
−1.352
1.00
63.41
N
ATOM
2591
C
LYS
E
77
−27.092
27.775
−5.458
1.00
52.74
C
ATOM
2592
O
LYS
E
77
−27.834
28.756
−5.373
1.00
53.10
O
ATOM
2593
N
LYS
E
78
−27.478
26.606
−5.971
1.00
52.29
N
ATOM
2594
CA
LYS
E
78
−28.781
26.376
−6.618
1.00
51.59
C
ATOM
2595
CB
LYS
E
78
−28.629
25.314
−7.701
1.00
51.61
C
ATOM
2596
CG
LYS
E
78
−27.597
25.644
−8.736
1.00
55.37
C
ATOM
2597
CD
LYS
E
78
−27.595
24.600
−9.828
1.00
60.45
C
ATOM
2598
CE
LYS
E
78
−26.265
24.629
−10.576
1.00
64.73
C
ATOM
2599
NZ
LYS
E
78
−26.241
23.689
−11.766
1.00
67.80
N
ATOM
2600
C
LYS
E
78
−29.925
25.946
−5.695
1.00
50.45
C
ATOM
2601
O
LYS
E
78
−31.070
25.859
−6.152
1.00
50.69
O
ATOM
2602
N
GLY
E
79
−29.622
25.633
−4.431
1.00
48.61
N
ATOM
2603
CA
GLY
E
79
−30.626
25.169
−3.467
1.00
46.20
C
ATOM
2604
C
GLY
E
79
−31.582
24.117
−4.026
1.00
45.27
C
ATOM
2605
O
GLY
E
79
−31.149
23.109
−4.600
1.00
42.86
O
ATOM
2606
N
ASP
E
80
−32.889
24.387
−3.878
1.00
45.12
N
ATOM
2607
CA
ASP
E
80
−33.971
23.474
−4.336
1.00
44.97
C
ATOM
2608
CB
ASP
E
80
−35.331
23.877
−3.733
1.00
45.06
C
ATOM
2609
CG
ASP
E
80
−35.385
23.621
−2.241
1.00
45.92
C
ATOM
2610
OD1
ASP
E
80
−34.552
22.805
−1.797
1.00
50.22
O
ATOM
2611
OD2
ASP
E
80
−36.209
24.215
−1.505
1.00
43.28
O
ATOM
2612
C
ASP
E
80
−34.055
23.260
−5.850
1.00
45.13
C
ATOM
2613
O
ASP
E
80
−34.584
22.247
−6.298
1.00
44.46
O
ATOM
2614
N
GLN
E
81
−33.486
24.186
−6.620
1.00
45.80
N
ATOM
2615
CA
GLN
E
81
−33.488
24.107
−8.089
1.00
46.94
C
ATOM
2616
CB
GLN
E
81
−33.388
25.513
−8.722
1.00
47.91
C
ATOM
2617
CG
GLN
E
81
−34.653
26.382
−8.648
1.00
49.80
C
ATOM
2618
CD
GLN
E
81
−35.031
26.756
−7.225
1.00
52.50
C
ATOM
2619
OE1
GLN
E
81
−34.201
27.259
−6.450
1.00
56.42
O
ATOM
2620
NE2
GLN
E
81
−36.271
26.508
−6.866
1.00
53.27
N
ATOM
2621
C
GLN
E
81
−32.354
23.226
−8.628
1.00
46.85
C
ATOM
2622
O
GLN
E
81
−32.232
23.038
−9.840
1.00
47.31
O
ATOM
2623
N
CYS
E
82
−31.532
22.660
−7.741
1.00
46.00
N
ATOM
2624
CA
CYS
E
82
−30.473
21.759
−8.197
1.00
44.71
C
ATOM
2625
CB
CYS
E
82
−29.479
21.471
−7.058
1.00
44.58
C
ATOM
2626
SG
CYS
E
82
−28.029
20.574
−7.678
1.00
44.34
S
ATOM
2627
C
CYS
E
82
−31.048
20.446
−8.726
1.00
44.24
C
ATOM
2628
O
CYS
E
82
−32.071
19.975
−8.225
1.00
44.60
O
ATOM
2629
N
GLU
E
83
−30.404
19.860
−9.739
1.00
43.02
N
ATOM
2630
CA
GLU
E
83
−30.808
18.571
−10.321
1.00
42.89
C
ATOM
2631
CB
GLU
E
83
−30.223
18.471
−11.729
1.00
43.36
C
ATOM
2632
CG
GLU
E
83
−29.088
19.514
−11.963
1.00
47.27
C
ATOM
2633
CD
GLU
E
83
−28.176
19.165
−13.153
1.00
48.75
C
ATOM
2634
OE1
GLU
E
83
−27.193
19.932
−13.395
1.00
55.39
O
ATOM
2635
OE2
GLU
E
83
−28.415
18.114
−13.830
1.00
55.23
O
ATOM
2636
C
GLU
E
83
−30.335
17.384
−9.494
1.00
39.93
C
ATOM
2637
O
GLU
E
83
−30.741
16.215
−9.687
1.00
39.21
O
ATOM
2638
N
PHE
E
84
−29.430
17.670
−8.570
1.00
37.89
N
ATOM
2639
CA
PHE
E
84
−28.891
16.613
−7.756
1.00
35.71
C
ATOM
2640
CB
PHE
E
84
−27.343
16.609
−7.806
1.00
35.62
C
ATOM
2641
CG
PHE
E
84
−26.766
16.461
−9.205
1.00
36.55
C
ATOM
2642
CD1
PHE
E
84
−26.238
17.561
−9.868
1.00
35.78
C
ATOM
2643
CE1
PHE
E
84
−25.683
17.440
−11.182
1.00
38.26
C
ATOM
2644
CZ
PHE
E
84
−25.649
16.207
−11.803
1.00
38.82
C
ATOM
2645
CE2
PHE
E
84
−26.161
15.078
−11.147
1.00
42.35
C
ATOM
2646
CD2
PHE
E
84
−26.716
15.210
−9.829
1.00
39.76
C
ATOM
2647
C
PHE
E
84
−29.455
16.778
−6.320
1.00
34.41
C
ATOM
2648
O
PHE
E
84
−29.864
17.860
−5.913
1.00
33.89
O
ATOM
2649
N
LEU
E
85
−29.455
15.676
−5.603
1.00
33.01
N
ATOM
2650
CA
LEU
E
85
−29.962
15.539
−4.242
1.00
34.42
C
ATOM
2651
CB
LEU
E
85
−29.888
14.039
−3.909
1.00
34.42
C
ATOM
2652
CG
LEU
E
85
−30.854
12.999
−3.361
1.00
38.28
C
ATOM
2653
CD1
LEU
E
85
−32.315
13.248
−3.771
1.00
39.00
C
ATOM
2654
CD2
LEU
E
85
−30.402
11.593
−3.836
1.00
34.69
C
ATOM
2655
C
LEU
E
85
−29.122
16.367
−3.237
1.00
34.30
C
ATOM
2656
O
LEU
E
85
−27.880
16.259
−3.198
1.00
33.65
O
ATOM
2657
N
HIS
E
86
−29.786
17.193
−2.434
1.00
33.63
N
ATOM
2658
CA
HIS
E
86
−29.142
17.847
−1.317
1.00
33.34
C
ATOM
2659
CB
HIS
E
86
−29.541
19.304
−1.260
1.00
32.70
C
ATOM
2660
CG
HIS
E
86
−28.884
20.172
−2.295
1.00
31.14
C
ATOM
2661
ND1
HIS
E
86
−28.827
21.541
−2.162
1.00
30.21
N
ATOM
2662
CE1
HIS
E
86
−28.204
22.066
−3.195
1.00
31.04
C
ATOM
2663
NE2
HIS
E
86
−27.817
21.077
−3.983
1.00
27.66
N
ATOM
2664
CD2
HIS
E
86
−28.236
19.883
−3.447
1.00
28.50
C
ATOM
2665
C
HIS
E
86
−29.508
17.096
−0.031
1.00
34.46
C
ATOM
2666
O
HIS
E
86
−30.227
17.602
0.834
1.00
34.31
O
ATOM
2667
N
GLU
E
87
−29.018
15.860
0.059
1.00
35.41
N
ATOM
2668
CA
GLU
E
87
−29.192
15.005
1.212
1.00
37.64
C
ATOM
2669
CB
GLU
E
87
−30.511
14.229
1.121
1.00
37.29
C
ATOM
2670
CG
GLU
E
87
−30.694
13.235
2.264
1.00
38.59
C
ATOM
2671
CD
GLU
E
87
−31.891
12.280
2.135
1.00
38.23
C
ATOM
2672
OE1
GLU
E
87
−32.573
12.259
1.077
1.00
35.85
O
ATOM
2673
OE2
GLU
E
87
−32.117
11.536
3.137
1.00
41.22
O
ATOM
2674
C
GLU
E
87
−28.040
13.999
1.175
1.00
39.03
C
ATOM
2675
O
GLU
E
87
−27.698
13.479
0.100
1.00
38.12
O
ATOM
2676
N
TYR
E
88
−27.453
13.683
2.329
1.00
40.99
N
ATOM
2677
CA
TYR
E
88
−26.438
12.647
2.306
1.00
43.56
C
ATOM
2678
CB
TYR
E
88
−25.405
12.692
3.460
1.00
44.72
C
ATOM
2679
CG
TYR
E
88
−24.238
11.718
3.169
1.00
47.61
C
ATOM
2680
CD1
TYR
E
88
−23.255
12.023
2.216
1.00
49.16
C
ATOM
2681
CE1
TYR
E
88
−22.220
11.110
1.913
1.00
48.23
C
ATOM
2682
CZ
TYR
E
88
−22.190
9.907
2.524
1.00
44.96
C
ATOM
2683
OH
TYR
E
88
−21.205
9.042
2.249
1.00
49.62
O
ATOM
2684
CE2
TYR
E
88
−23.132
9.561
3.470
1.00
49.06
C
ATOM
2685
CD2
TYR
E
88
−24.161
10.464
3.790
1.00
48.49
C
ATOM
2686
C
TYR
E
88
−27.123
11.341
2.243
1.00
44.32
C
ATOM
2687
O
TYR
E
88
−27.732
10.920
3.203
1.00
45.92
O
ATOM
2688
N
ASP
E
89
−27.039
10.698
1.093
1.00
45.86
N
ATOM
2689
CA
ASP
E
89
−27.430
9.313
0.980
1.00
47.31
C
ATOM
2690
CB
ASP
E
89
−28.644
9.171
0.048
1.00
46.75
C
ATOM
2691
CG
ASP
E
89
−29.146
7.733
−0.071
1.00
47.59
C
ATOM
2692
OD1
ASP
E
89
−28.410
6.765
0.237
1.00
46.06
O
ATOM
2693
OD2
ASP
E
89
−30.306
7.566
−0.503
1.00
50.29
O
ATOM
2694
C
ASP
E
89
−26.221
8.580
0.428
1.00
48.29
C
ATOM
2695
O
ASP
E
89
−25.901
8.717
−0.747
1.00
47.55
O
ATOM
2696
N
MET
E
90
−25.566
7.805
1.295
1.00
50.53
N
ATOM
2697
CA
MET
E
90
−24.346
7.060
0.956
1.00
53.26
C
ATOM
2698
CB
MET
E
90
−23.756
6.309
2.188
1.00
53.27
C
ATOM
2699
CG
MET
E
90
−24.552
5.053
2.647
1.00
56.70
C
ATOM
2700
SD
MET
E
90
−24.136
4.344
4.281
1.00
58.92
S
ATOM
2701
CE
MET
E
90
−22.763
3.255
3.864
1.00
60.49
C
ATOM
2702
C
MET
E
90
−24.551
6.100
−0.214
1.00
52.16
C
ATOM
2703
O
MET
E
90
−23.581
5.736
−0.879
1.00
52.83
O
ATOM
2704
N
THR
E
91
−25.810
5.715
−0.474
1.00
51.03
N
ATOM
2705
CA
THR
E
91
−26.135
4.762
−1.551
1.00
49.35
C
ATOM
2706
CB
THR
E
91
−27.402
3.887
−1.243
1.00
49.74
C
ATOM
2707
OG1
THR
E
91
−28.539
4.732
−1.018
1.00
49.46
O
ATOM
2708
CG2
THR
E
91
−27.172
3.001
−0.031
1.00
50.99
C
ATOM
2709
C
THR
E
91
−26.377
5.443
−2.873
1.00
47.57
C
ATOM
2710
O
THR
E
91
−26.556
4.765
−3.900
1.00
47.97
O
ATOM
2711
N
LYS
E
92
−26.410
6.773
−2.870
1.00
44.84
N
ATOM
2712
CA
LYS
E
92
−26.694
7.493
−4.110
1.00
42.64
C
ATOM
2713
CB
LYS
E
92
−28.060
8.202
−4.052
1.00
42.47
C
ATOM
2714
CG
LYS
E
92
−29.239
7.224
−4.140
1.00
43.53
C
ATOM
2715
CD
LYS
E
92
−30.550
7.958
−4.021
1.00
46.74
C
ATOM
2716
CE
LYS
E
92
−31.751
7.118
−4.485
1.00
49.77
C
ATOM
2717
NZ
LYS
E
92
−32.896
8.037
−4.867
1.00
50.02
N
ATOM
2718
C
LYS
E
92
−25.573
8.457
−4.501
1.00
40.10
C
ATOM
2719
O
LYS
E
92
−25.796
9.458
−5.136
1.00
38.93
O
ATOM
2720
N
MET
E
93
−24.349
8.133
−4.122
1.00
39.27
N
ATOM
2721
CA
MET
E
93
−23.235
9.034
−4.437
1.00
36.91
C
ATOM
2722
CB
MET
E
93
−22.119
8.773
−3.412
1.00
37.41
C
ATOM
2723
CG
MET
E
93
−22.479
9.291
−1.964
1.00
31.53
C
ATOM
2724
SD
MET
E
93
−22.304
11.036
−1.841
1.00
28.70
S
ATOM
2725
CE
MET
E
93
−20.484
11.169
−1.694
1.00
34.53
C
ATOM
2726
C
MET
E
93
−22.765
8.825
−5.899
1.00
37.37
C
ATOM
2727
O
MET
E
93
−22.918
7.710
−6.447
1.00
36.91
O
ATOM
2728
N
PRO
E
94
−22.165
9.857
−6.536
1.00
36.94
N
ATOM
2729
CA
PRO
E
94
−21.564
9.531
−7.838
1.00
37.19
C
ATOM
2730
CB
PRO
E
94
−21.254
10.895
−8.461
1.00
36.24
C
ATOM
2731
CG
PRO
E
94
−20.950
11.736
−7.389
1.00
38.23
C
ATOM
2732
CD
PRO
E
94
−21.988
11.296
−6.224
1.00
39.37
C
ATOM
2733
C
PRO
E
94
−20.320
8.631
−7.811
1.00
36.57
C
ATOM
2734
O
PRO
E
94
−19.810
8.256
−6.737
1.00
35.69
O
ATOM
2735
N
GLU
E
95
−19.914
8.226
−9.014
1.00
35.80
N
ATOM
2736
CA
GLU
E
95
−18.753
7.391
−9.223
1.00
35.27
C
ATOM
2737
CB
GLU
E
95
−18.713
6.907
−10.675
1.00
35.38
C
ATOM
2738
CG
GLU
E
95
−17.861
5.669
−10.825
1.00
38.08
C
ATOM
2739
CD
GLU
E
95
−17.766
5.134
−12.274
1.00
40.77
C
ATOM
2740
OE1
GLU
E
95
−18.593
5.507
−13.149
1.00
46.42
O
ATOM
2741
OE2
GLU
E
95
−16.839
4.316
−12.507
1.00
46.20
O
ATOM
2742
C
GLU
E
95
−17.498
8.196
−8.913
1.00
31.36
C
ATOM
2743
O
GLU
E
95
−17.424
9.384
−9.207
1.00
31.21
O
ATOM
2744
N
CYS
E
96
−16.527
7.556
−8.294
1.00
29.43
N
ATOM
2745
CA
CYS
E
96
−15.284
8.265
−7.889
1.00
28.13
C
ATOM
2746
CB
CYS
E
96
−14.508
7.365
−6.971
1.00
27.21
C
ATOM
2747
SG
CYS
E
96
−12.849
7.953
−6.549
1.00
27.50
S
ATOM
2748
C
CYS
E
96
−14.508
8.471
−9.175
1.00
27.70
C
ATOM
2749
O
CYS
E
96
−14.232
7.501
−9.836
1.00
27.84
O
ATOM
2750
N
TYR
E
97
−14.181
9.703
−9.531
1.00
26.25
N
ATOM
2751
CA
TYR
E
97
−13.414
9.932
−10.745
1.00
27.57
C
ATOM
2752
CB
TYR
E
97
−13.183
11.447
−10.963
1.00
27.83
C
ATOM
2753
CG
TYR
E
97
−12.434
11.765
−12.280
1.00
27.33
C
ATOM
2754
CD1
TYR
E
97
−13.144
11.989
−13.471
1.00
27.83
C
ATOM
2755
CE1
TYR
E
97
−12.478
12.267
−14.677
1.00
27.62
C
ATOM
2756
CZ
TYR
E
97
−11.082
12.321
−14.685
1.00
28.27
C
ATOM
2757
OH
TYR
E
97
−10.432
12.605
−15.880
1.00
25.71
O
ATOM
2758
CE2
TYR
E
97
−10.354
12.103
−13.511
1.00
24.85
C
ATOM
2759
CD2
TYR
E
97
−11.038
11.817
−12.316
1.00
26.24
C
ATOM
2760
C
TYR
E
97
−12.073
9.203
−10.758
1.00
28.02
C
ATOM
2761
O
TYR
E
97
−11.659
8.599
−11.805
1.00
27.69
O
ATOM
2762
N
PHE
E
98
−11.400
9.205
−9.593
1.00
28.03
N
ATOM
2763
CA
PHE
E
98
−10.056
8.574
−9.539
1.00
28.74
C
ATOM
2764
CB
PHE
E
98
−9.209
9.067
−8.348
1.00
27.42
C
ATOM
2765
CG
PHE
E
98
−8.924
10.529
−8.429
1.00
27.64
C
ATOM
2766
CD1
PHE
E
98
−7.877
11.006
−9.197
1.00
23.70
C
ATOM
2767
CE1
PHE
E
98
−7.658
12.398
−9.317
1.00
26.52
C
ATOM
2768
CZ
PHE
E
98
−8.497
13.304
−8.674
1.00
28.09
C
ATOM
2769
CE2
PHE
E
98
−9.562
12.831
−7.920
1.00
28.78
C
ATOM
2770
CD2
PHE
E
98
−9.789
11.454
−7.817
1.00
28.89
C
ATOM
2771
C
PHE
E
98
−10.123
7.079
−9.657
1.00
29.39
C
ATOM
2772
O
PHE
E
98
−9.326
6.464
−10.377
1.00
29.21
O
ATOM
2773
N
TYR
E
99
−11.082
6.463
−8.980
1.00
30.20
N
ATOM
2774
CA
TYR
E
99
−11.204
5.035
−9.147
1.00
31.46
C
ATOM
2775
CB
TYR
E
99
−12.314
4.476
−8.289
1.00
32.90
C
ATOM
2776
CG
TYR
E
99
−12.154
3.001
−8.112
1.00
35.08
C
ATOM
2777
CD1
TYR
E
99
−11.241
2.484
−7.198
1.00
34.37
C
ATOM
2778
CE1
TYR
E
99
−11.089
1.106
−7.057
1.00
36.08
C
ATOM
2779
CZ
TYR
E
99
−11.825
0.251
−7.867
1.00
36.77
C
ATOM
2780
OH
TYR
E
99
−11.700
−1.119
−7.754
1.00
39.62
O
ATOM
2781
CE2
TYR
E
99
−12.712
0.738
−8.781
1.00
38.21
C
ATOM
2782
CD2
TYR
E
99
−12.871
2.107
−8.916
1.00
36.36
C
ATOM
2783
C
TYR
E
99
−11.462
4.646
−10.616
1.00
32.82
C
ATOM
2784
O
TYR
E
99
−10.908
3.659
−11.120
1.00
32.79
O
ATOM
2785
N
SER
E
100
−12.332
5.389
−11.280
1.00
33.86
N
ATOM
2786
CA
SER
E
100
−12.687
5.068
−12.670
1.00
35.38
C
ATOM
2787
CB
SER
E
100
−13.824
5.936
−13.129
1.00
35.98
C
ATOM
2788
OG
SER
E
100
−14.948
5.495
−12.418
1.00
42.18
O
ATOM
2789
C
SER
E
100
−11.552
5.261
−13.634
1.00
34.57
C
ATOM
2790
O
SER
E
100
−11.311
4.382
−14.485
1.00
35.38
O
ATOM
2791
N
LYS
E
101
−10.898
6.419
−13.544
1.00
33.48
N
ATOM
2792
CA
LYS
E
101
−9.846
6.763
−14.475
1.00
33.32
C
ATOM
2793
CB
LYS
E
101
−9.693
8.273
−14.596
1.00
32.76
C
ATOM
2794
CG
LYS
E
101
−10.919
8.921
−15.140
1.00
35.61
C
ATOM
2795
CD
LYS
E
101
−11.059
8.628
−16.629
1.00
39.82
C
ATOM
2796
CE
LYS
E
101
−12.355
9.151
−17.199
1.00
42.68
C
ATOM
2797
NZ
LYS
E
101
−12.484
8.574
−18.576
1.00
42.39
N
ATOM
2798
C
LYS
E
101
−8.497
6.108
−14.191
1.00
33.88
C
ATOM
2799
O
LYS
E
101
−7.759
5.832
−15.139
1.00
33.90
O
ATOM
2800
N
PHE
E
102
−8.181
5.861
−12.912
1.00
32.56
N
ATOM
2801
CA
PHE
E
102
−6.835
5.447
−12.503
1.00
31.86
C
ATOM
2802
CB
PHE
E
102
−6.209
6.431
−11.495
1.00
31.71
C
ATOM
2803
CG
PHE
E
102
−5.911
7.752
−12.070
1.00
29.81
C
ATOM
2804
CD1
PHE
E
102
−4.669
8.009
−12.648
1.00
30.67
C
ATOM
2805
CE1
PHE
E
102
−4.383
9.228
−13.206
1.00
31.08
C
ATOM
2806
CZ
PHE
E
102
−5.313
10.210
−13.239
1.00
29.85
C
ATOM
2807
CE2
PHE
E
102
−6.592
9.960
−12.677
1.00
32.46
C
ATOM
2808
CD2
PHE
E
102
−6.855
8.741
−12.088
1.00
30.80
C
ATOM
2809
C
PHE
E
102
−6.867
4.069
−11.922
1.00
32.42
C
ATOM
2810
O
PHE
E
102
−5.820
3.478
−11.671
1.00
33.02
O
ATOM
2811
N
GLY
E
103
−8.068
3.525
−11.746
1.00
31.07
N
ATOM
2812
CA
GLY
E
103
−8.200
2.204
−11.153
1.00
31.68
C
ATOM
2813
C
GLY
E
103
−7.805
2.110
−9.684
1.00
31.41
C
ATOM
2814
O
GLY
E
103
−7.611
1.003
−9.152
1.00
31.06
O
ATOM
2815
N
GLU
E
104
−7.663
3.257
−9.019
1.00
29.83
N
ATOM
2816
CA
GLU
E
104
−7.265
3.253
−7.620
1.00
30.89
C
ATOM
2817
CB
GLU
E
104
−5.732
3.019
−7.469
1.00
29.78
C
ATOM
2818
CG
GLU
E
104
−4.916
4.241
−7.780
1.00
33.61
C
ATOM
2819
CD
GLU
E
104
−3.398
4.038
−7.615
1.00
36.14
C
ATOM
2820
OE1
GLU
E
104
−2.709
3.917
−8.663
1.00
46.90
O
ATOM
2821
OE2
GLU
E
104
−2.887
3.988
−6.469
1.00
39.91
O
ATOM
2822
C
GLU
E
104
−7.690
4.595
−7.001
1.00
29.61
C
ATOM
2823
O
GLU
E
104
−7.924
5.573
−7.706
1.00
28.68
O
ATOM
2824
N
CYS
E
105
−7.825
4.607
−5.671
1.00
29.11
N
ATOM
2825
CA
CYS
E
105
−8.246
5.809
−4.944
1.00
28.00
C
ATOM
2826
CB
CYS
E
105
−9.773
5.777
−4.754
1.00
28.22
C
ATOM
2827
SG
CYS
E
105
−10.400
7.210
−3.819
1.00
26.77
S
ATOM
2828
C
CYS
E
105
−7.535
5.815
−3.584
1.00
27.95
C
ATOM
2829
O
CYS
E
105
−7.514
4.801
−2.897
1.00
25.98
O
ATOM
2830
N
SER
E
106
−6.951
6.947
−3.213
1.00
27.07
N
ATOM
2831
CA
SER
E
106
−6.105
7.032
−1.999
1.00
27.68
C
ATOM
2832
CB
SER
E
106
−5.147
8.214
−2.106
1.00
28.93
C
ATOM
2833
OG
SER
E
106
−4.158
8.061
−3.082
1.00
32.26
O
ATOM
2834
C
SER
E
106
−6.926
7.262
−0.708
1.00
27.48
C
ATOM
2835
O
SER
E
106
−6.392
7.202
0.389
1.00
25.89
O
ATOM
2836
N
ASN
E
107
−8.224
7.543
−0.847
1.00
27.00
N
ATOM
2837
CA
ASN
E
107
−9.022
7.880
0.340
1.00
27.38
C
ATOM
2838
CB
ASN
E
107
−10.085
8.933
−0.017
1.00
25.51
C
ATOM
2839
CG
ASN
E
107
−10.890
9.409
1.197
1.00
27.22
C
ATOM
2840
OD1
ASN
E
107
−10.602
9.029
2.353
1.00
25.23
O
ATOM
2841
ND2
ASN
E
107
−11.888
10.253
0.951
1.00
23.13
N
ATOM
2842
C
ASN
E
107
−9.615
6.620
0.922
1.00
26.72
C
ATOM
2843
O
ASN
E
107
−10.527
6.051
0.323
1.00
27.32
O
ATOM
2844
N
LYS
E
108
−9.112
6.171
2.083
1.00
27.29
N
ATOM
2845
CA
LYS
E
108
−9.675
4.967
2.740
1.00
28.64
C
ATOM
2846
CB
LYS
E
108
−9.005
4.634
4.084
1.00
29.14
C
ATOM
2847
CG
LYS
E
108
−7.538
4.411
4.047
1.00
32.85
C
ATOM
2848
CD
LYS
E
108
−7.002
4.055
5.424
1.00
35.90
C
ATOM
2849
CE
LYS
E
108
−5.512
4.069
5.365
1.00
36.28
C
ATOM
2850
NZ
LYS
E
108
−4.896
4.177
6.709
1.00
38.68
N
ATOM
2851
C
LYS
E
108
−11.169
5.115
3.022
1.00
28.54
C
ATOM
2852
O
LYS
E
108
−11.874
4.132
3.143
1.00
28.63
O
ATOM
2853
N
GLU
E
109
−11.635
6.345
3.166
1.00
28.33
N
ATOM
2854
CA
GLU
E
109
−13.047
6.575
3.462
1.00
29.24
C
ATOM
2855
CB
GLU
E
109
−13.216
7.516
4.691
1.00
30.12
C
ATOM
2856
CG
GLU
E
109
−12.867
6.879
6.081
1.00
35.42
C
ATOM
2857
CD
GLU
E
109
−11.375
6.836
6.374
1.00
39.45
C
ATOM
2858
OE1
GLU
E
109
−10.711
7.883
6.247
1.00
43.20
O
ATOM
2859
OE2
GLU
E
109
−10.867
5.756
6.753
1.00
42.90
O
ATOM
2860
C
GLU
E
109
−13.729
7.224
2.273
1.00
26.67
C
ATOM
2861
O
GLU
E
109
−14.689
7.956
2.466
1.00
27.77
O
ATOM
2862
N
CYS
E
110
−13.258
6.987
1.039
1.00
25.08
N
ATOM
2863
CA
CYS
E
110
−13.932
7.567
−0.125
1.00
22.73
C
ATOM
2864
CB
CYS
E
110
−13.376
7.014
−1.473
1.00
22.38
C
ATOM
2865
SG
CYS
E
110
−14.027
7.983
−2.730
1.00
25.05
S
ATOM
2866
C
CYS
E
110
−15.435
7.227
−0.065
1.00
23.60
C
ATOM
2867
O
CYS
E
110
−15.792
6.066
0.033
1.00
22.90
O
ATOM
2868
N
PRO
E
111
−16.302
8.231
−0.103
1.00
25.41
N
ATOM
2869
CA
PRO
E
111
−17.756
7.947
−0.173
1.00
26.31
C
ATOM
2870
CB
PRO
E
111
−18.338
9.189
0.451
1.00
25.57
C
ATOM
2871
CG
PRO
E
111
−17.444
10.247
−0.107
1.00
26.34
C
ATOM
2872
CD
PRO
E
111
−16.056
9.690
−0.017
1.00
24.13
C
ATOM
2873
C
PRO
E
111
−18.303
7.806
−1.607
1.00
28.09
C
ATOM
2874
O
PRO
E
111
−19.532
7.606
−1.781
1.00
29.35
O
ATOM
2875
N
PHE
E
112
−17.433
7.912
−2.620
1.00
27.81
N
ATOM
2876
CA
PHE
E
112
−17.882
7.841
−4.035
1.00
28.90
C
ATOM
2877
CB
PHE
E
112
−17.134
8.827
−4.915
1.00
27.89
C
ATOM
2878
CG
PHE
E
112
−17.352
10.241
−4.519
1.00
29.43
C
ATOM
2879
CD1
PHE
E
112
−18.534
10.897
−4.864
1.00
29.20
C
ATOM
2880
CE1
PHE
E
112
−18.766
12.200
−4.465
1.00
31.44
C
ATOM
2881
CZ
PHE
E
112
−17.793
12.893
−3.678
1.00
33.51
C
ATOM
2882
CE2
PHE
E
112
−16.595
12.222
−3.336
1.00
36.00
C
ATOM
2883
CD2
PHE
E
112
−16.403
10.905
−3.756
1.00
32.00
C
ATOM
2884
C
PHE
E
112
−17.782
6.434
−4.538
1.00
30.08
C
ATOM
2885
O
PHE
E
112
−17.062
5.634
−3.968
1.00
29.81
O
ATOM
2886
N
LEU
E
113
−18.581
6.077
−5.546
1.00
32.91
N
ATOM
2887
CA
LEU
E
113
−18.669
4.649
−5.892
1.00
35.90
C
ATOM
2888
CB
LEU
E
113
−19.833
4.379
−6.828
1.00
37.47
C
ATOM
2889
CG
LEU
E
113
−21.292
4.429
−6.377
1.00
41.02
C
ATOM
2890
CD1
LEU
E
113
−21.876
3.209
−7.053
1.00
44.71
C
ATOM
2891
CD2
LEU
E
113
−21.536
4.386
−4.840
1.00
43.90
C
ATOM
2892
C
LEU
E
113
−17.391
4.132
−6.538
1.00
36.02
C
ATOM
2893
O
LEU
E
113
−16.829
4.764
−7.434
1.00
36.35
O
ATOM
2894
N
HIS
E
114
−16.931
2.977
−6.089
1.00
36.99
N
ATOM
2895
CA
HIS
E
114
−15.750
2.409
−6.678
1.00
37.82
C
ATOM
2896
CB
HIS
E
114
−14.693
2.014
−5.614
1.00
36.44
C
ATOM
2897
CG
HIS
E
114
−13.917
3.183
−5.031
1.00
30.06
C
ATOM
2898
ND1
HIS
E
114
−12.967
3.009
−4.046
1.00
27.67
N
ATOM
2899
CE1
HIS
E
114
−12.448
4.177
−3.706
1.00
29.37
C
ATOM
2900
NE2
HIS
E
114
−12.992
5.119
−4.459
1.00
21.70
N
ATOM
2901
CD2
HIS
E
114
−13.942
4.521
−5.284
1.00
28.54
C
ATOM
2902
C
HIS
E
114
−16.206
1.255
−7.575
1.00
41.48
C
ATOM
2903
O
HIS
E
114
−16.540
0.141
−7.109
1.00
41.75
O
ATOM
2904
N
ILE
E
115
−16.225
1.542
−8.874
1.00
45.09
N
ATOM
2905
CA
ILE
E
115
−16.770
0.592
−9.829
1.00
48.98
C
ATOM
2906
CB
ILE
E
115
−17.879
1.233
−10.682
1.00
48.73
C
ATOM
2907
CG1
ILE
E
115
−19.018
1.650
−9.769
1.00
49.30
C
ATOM
2908
CD1
ILE
E
115
−20.108
2.486
−10.414
1.00
52.31
C
ATOM
2909
CG2
ILE
E
115
−18.429
0.233
−11.703
1.00
50.04
C
ATOM
2910
C
ILE
E
115
−15.698
−0.097
−10.663
1.00
51.45
C
ATOM
2911
O
ILE
E
115
−14.888
0.552
−11.342
1.00
51.91
O
ATOM
2912
N
ASP
E
116
−15.713
−1.426
−10.604
1.00
55.09
N
ATOM
2913
CA
ASP
E
116
−14.838
−2.269
−11.446
1.00
58.10
C
ATOM
2914
CB
ASP
E
116
−14.477
−3.551
−10.704
1.00
57.84
C
ATOM
2915
CG
ASP
E
116
−13.320
−3.361
−9.748
1.00
59.39
C
ATOM
2916
OD1
ASP
E
116
−12.283
−2.772
−10.153
1.00
58.51
O
ATOM
2917
OD2
ASP
E
116
−13.450
−3.816
−8.591
1.00
61.50
O
ATOM
2918
C
ASP
E
116
−15.346
−2.612
−12.862
1.00
59.18
C
ATOM
2919
O
ASP
E
116
−14.564
−2.484
−13.826
1.00
59.43
O
ATOM
2920
N
PRO
E
117
−16.632
−3.068
−12.982
1.00
60.29
N
ATOM
2921
CA
PRO
E
117
−17.292
−3.632
−14.189
1.00
61.09
C
ATOM
2922
CB
PRO
E
117
−18.750
−3.133
−14.046
1.00
61.33
C
ATOM
2923
CG
PRO
E
117
−18.991
−3.196
−12.535
1.00
60.80
C
ATOM
2924
CD
PRO
E
117
−17.592
−3.089
−11.852
1.00
60.62
C
ATOM
2925
C
PRO
E
117
−16.713
−3.318
−15.593
1.00
62.20
C
ATOM
2926
O
PRO
E
117
−16.501
−2.150
−15.971
1.00
62.74
O
ATOM
2927
OXT
PRO
E
117
−16.466
−4.245
−16.386
1.00
62.43
O
ATOM
2928
ZN
ZN
E
502
−12.635
7.037
−4.437
1.00
27.25
ZN
ATOM
2929
ZN
ZN
E
501
−26.608
21.029
−5.804
1.00
39.92
ZN
ATOM
2930
OH2
HOH
W
1
−17.549
40.654
24.318
1.00
31.56
ATOM
2931
OH2
HOH
W
2
17.362
20.052
−2.479
1.00
25.50
ATOM
2932
OH2
HOH
W
3
−2.011
29.501
11.491
1.00
30.11
ATOM
2933
OH2
HOH
W
4
−1.231
11.877
4.344
1.00
33.10
ATOM
2934
OH2
HOH
W
5
−15.837
4.131
−2.007
1.00
34.35
ATOM
2935
OH2
HOH
W
6
−18.878
24.607
32.037
1.00
37.33
ATOM
2936
OH2
HOH
W
7
−8.008
1.692
−4.434
1.00
36.76
ATOM
2937
OH2
HOH
W
8
0.580
21.608
13.618
1.00
37.53
ATOM
2938
OH2
HOH
W
9
16.380
17.882
10.672
1.00
37.87
ATOM
2939
OH2
HOH
W
10
−22.130
37.815
21.073
1.00
35.89
ATOM
2940
OH2
HOH
W
11
4.673
13.758
−32.750
1.00
33.95
ATOM
2941
OH2
HOH
W
12
−20.499
24.465
5.437
1.00
28.59
ATOM
2942
OH2
HOH
W
13
23.425
25.428
−2.508
1.00
37.38
ATOM
2943
OH2
HOH
W
14
−14.983
15.840
−4.699
1.00
46.26
ATOM
2944
OH2
HOH
W
15
−10.233
9.257
−27.822
1.00
38.63
ATOM
2945
OH2
HOH
W
16
−21.192
34.424
12.062
1.00
37.61
ATOM
2946
OH2
HOH
W
17
0.053
26.141
−3.950
1.00
54.93
ATOM
2947
OH2
HOH
W
18
−5.394
4.386
9.736
1.00
37.09
ATOM
2948
OH2
HOH
W
19
−8.975
14.385
−2.075
1.00
37.40
ATOM
2949
OH2
HOH
W
20
−11.483
11.732
−4.064
1.00
48.02
ATOM
2950
OH2
HOH
W
21
8.538
14.250
−15.163
1.00
45.77
ATOM
2951
OH2
HOH
W
22
−13.507
26.363
33.684
1.00
36.52
ATOM
2952
OH2
HOH
W
23
−22.909
39.389
25.431
1.00
51.50
ATOM
2953
OH2
HOH
W
24
−6.016
34.962
15.554
1.00
40.08
ATOM
2954
OH2
HOH
W
25
−27.799
20.311
13.356
1.00
40.64
ATOM
2955
OH2
HOH
W
26
−9.659
40.204
28.277
1.00
50.22
ATOM
2956
OH2
HOH
W
27
−22.574
19.101
15.450
1.00
47.34
ATOM
2957
OH2
HOH
W
28
−37.126
26.264
−0.600
1.00
39.56
ATOM
2958
OH2
HOH
W
29
−9.898
30.112
1.970
1.00
56.19
ATOM
2959
OH2
HOH
W
30
14.875
14.573
−3.591
1.00
37.15
ATOM
2960
OH2
HOH
W
31
−1.553
2.908
9.016
1.00
47.01
ATOM
2961
OH2
HOH
W
32
−21.032
30.547
7.051
1.00
40.04
ATOM
2962
OH2
HOH
W
33
−0.209
7.321
−31.105
1.00
38.83
ATOM
2963
OH2
HOH
W
34
−9.687
37.554
14.224
1.00
43.90
ATOM
2964
OH2
HOH
W
35
−22.793
14.964
−8.325
1.00
50.86
ATOM
2965
OH2
HOH
W
36
−8.615
28.359
−20.387
1.00
40.23
ATOM
2966
OH2
HOH
W
37
−14.482
27.081
1.103
1.00
48.65
ATOM
2967
OH2
HOH
W
38
−21.411
9.115
−11.631
1.00
44.01
ATOM
2968
OH2
HOH
W
39
−11.464
1.095
−12.508
1.00
45.05
ATOM
2969
OH2
HOH
W
40
−0.402
15.047
−34.444
1.00
41.68
ATOM
2970
OH2
HOH
W
41
13.970
29.824
−18.438
1.00
46.66
ATOM
2971
OH2
HOH
W
42
0.010
18.179
−1.761
1.00
44.33
ATOM
2972
OH2
HOH
W
43
−24.141
42.098
27.887
1.00
62.32
ATOM
2973
OH2
HOH
W
44
−28.543
34.801
14.268
1.00
48.79
ATOM
2974
OH2
HOH
W
45
−19.052
36.669
14.149
1.00
43.38
ATOM
2975
OH2
HOH
W
46
−21.027
5.982
−0.187
1.00
43.29
ATOM
2976
OH2
HOH
W
47
−11.461
10.710
26.650
1.00
45.24
ATOM
2977
OH2
HOH
W
48
−32.578
9.524
−0.486
1.00
62.86
ATOM
2978
OH2
HOH
W
49
−25.755
40.650
29.914
1.00
48.32
ATOM
2979
OH2
HOH
W
50
−1.405
33.346
−4.925
1.00
60.35
ATOM
2980
OH2
HOH
W
51
−5.133
15.525
3.092
1.00
32.86
ATOM
2981
OH2
HOH
W
52
−13.645
18.564
32.922
1.00
50.50
ATOM
2982
OH2
HOH
W
53
−12.789
9.521
30.610
1.00
53.37
ATOM
2983
OH2
HOH
W
54
−9.573
17.794
28.093
1.00
49.45
ATOM
2984
OH2
HOH
W
55
−12.428
24.883
−14.429
1.00
43.17
ATOM
2985
OH2
HOH
W
56
−27.927
17.852
13.258
1.00
49.70
ATOM
2986
OH2
HOH
W
57
2.388
8.886
18.777
1.00
45.10
ATOM
2987
OH2
HOH
W
58
−12.077
0.367
−3.463
1.00
44.30
ATOM
2988
OW0
HOH
W
59
1.704
8.508
14.181
1.00
30.60
ATOM
2989
OW0
HOH
W
60
−7.056
24.808
−1.087
1.00
33.17
ATOM
2990
OW0
HOH
W
61
−12.392
10.737
−1.805
1.00
34.81
ATOM
2991
OW0
HOH
W
62
−2.525
5.036
5.866
1.00
36.96
ATOM
2992
OW0
HOH
W
63
−12.292
41.162
28.775
1.00
28.15
ATOM
2993
OW0
HOH
W
64
−7.563
19.859
7.620
1.00
29.26
ATOM
2994
OW0
HOH
W
65
−15.842
2.676
−14.366
1.00
53.47
ATOM
2995
OW0
HOH
W
66
−31.515
20.265
−4.155
1.00
35.35
ATOM
2996
OW0
HOH
W
67
−3.936
8.455
−26.236
1.00
32.60
ATOM
2997
OW0
HOH
W
68
−11.026
3.554
−0.830
1.00
40.04
ATOM
2998
OW0
HOH
W
69
−19.858
20.494
4.314
1.00
31.44
ATOM
2999
OW0
HOH
W
70
8.620
14.453
−26.618
1.00
35.55
ATOM
3000
OW0
HOH
W
71
−2.280
13.892
6.137
1.00
38.09
ATOM
3001
OW0
HOH
W
72
4.718
30.472
−24.432
1.00
38.03
ATOM
3002
OW0
HOH
W
73
−5.982
20.628
−1.464
1.00
46.93
ATOM
3003
OW0
HOH
W
74
3.340
20.902
4.854
1.00
37.94
ATOM
3004
OW0
HOH
W
75
18.667
21.796
−0.422
1.00
35.98
ATOM
3005
OW0
HOH
W
76
−9.114
7.695
8.920
1.00
46.41
ATOM
3006
OW0
HOH
W
77
−2.725
9.410
−24.189
1.00
35.50
ATOM
3007
OW0
HOH
W
78
26.980
18.899
12.829
1.00
31.81
ATOM
3008
OW0
HOH
W
79
17.646
21.683
3.437
1.00
31.91
ATOM
3009
OW0
HOH
W
80
−8.571
17.509
−24.553
1.00
34.33
ATOM
3010
OW0
HOH
W
81
−7.652
32.985
8.726
1.00
43.98
ATOM
3011
OW0
HOH
W
82
−2.625
5.632
−10.150
1.00
36.97
ATOM
3012
OW0
HOH
W
83
−12.028
32.276
7.227
1.00
39.35
ATOM
3013
OW0
HOH
W
84
−33.711
27.130
−3.174
1.00
42.56
ATOM
3014
OW0
HOH
W
85
−17.611
17.995
17.184
1.00
34.50
ATOM
3015
OW0
HOH
W
86
−19.109
18.971
27.592
1.00
35.69
ATOM
3016
OW0
HOH
W
87
−21.991
22.413
5.160
1.00
39.27
ATOM
3017
OW0
HOH
W
88
13.659
19.242
−8.046
1.00
47.60
ATOM
3018
OW0
HOH
W
89
−10.339
18.565
25.687
1.00
42.43
ATOM
3019
OW0
HOH
W
90
1.970
26.030
6.048
1.00
40.39
ATOM
3020
OW0
HOH
W
91
−8.765
21.673
0.433
1.00
37.72
ATOM
3021
OW0
HOH
W
92
−20.850
26.325
2.908
1.00
56.35
ATOM
3022
OW0
HOH
W
93
−12.366
9.191
20.494
1.00
34.84
ATOM
3023
OW0
HOH
W
94
−9.896
37.447
29.444
1.00
34.76
ATOM
3024
OW0
HOH
W
95
−17.552
18.919
−5.164
1.00
41.85
ATOM
3025
OW0
HOH
W
96
6.232
22.128
−7.201
1.00
41.21
ATOM
3026
OW0
HOH
W
97
−6.797
16.849
0.240
1.00
36.86
ATOM
3027
OW0
HOH
W
98
1.161
18.227
−5.047
1.00
57.06
ATOM
3028
OW0
HOH
W
99
2.288
6.066
6.745
1.00
37.06
ATOM
3029
OW0
HOH
W
100
−29.295
32.635
11.013
1.00
43.96
ATOM
3030
OW0
HOH
W
101
−28.464
25.424
7.690
1.00
45.49
ATOM
3031
OW0
HOH
W
102
−30.152
13.612
−9.680
1.00
43.80
ATOM
3032
OW0
HOH
W
103
−1.599
6.868
17.329
1.00
42.18
ATOM
3033
OW0
HOH
W
104
−1.887
24.290
18.531
1.00
44.13
ATOM
3034
OW0
HOH
W
105
27.796
19.455
3.634
1.00
48.46
ATOM
3035
OW0
HOH
W
106
−8.030
10.167
−31.332
1.00
48.25
ATOM
3036
OW0
HOH
W
107
−2.985
30.050
15.427
1.00
49.05
ATOM
3037
OW0
HOH
W
108
−1.504
32.061
−21.190
1.00
44.44
ATOM
3038
OW0
HOH
W
109
6.204
30.000
−16.933
1.00
42.31
ATOM
3039
OW0
HOH
W
110
−4.122
20.605
23.054
1.00
41.35
ATOM
3040
OW0
HOH
W
111
−9.885
40.341
21.208
1.00
43.88
ATOM
3041
OW0
HOH
W
112
−20.863
15.617
19.646
1.00
52.25
ATOM
3042
OW0
HOH
W
113
−27.560
21.675
7.325
1.00
36.97
ATOM
3043
OW0
HOH
W
114
−13.970
38.207
15.196
1.00
36.20
ATOM
3044
OW0
HOH
W
115
−10.257
8.670
16.396
1.00
44.34
ATOM
3045
OW0
HOH
W
116
−26.779
32.379
17.536
1.00
46.46
ATOM
3046
OW0
HOH
W
117
14.378
29.066
−14.762
1.00
43.06
ATOM
3047
OW0
HOH
W
118
−19.826
37.668
18.886
1.00
43.88
ATOM
3048
OW0
HOH
W
119
7.366
26.176
−46.829
1.00
49.36
ATOM
3049
OW0
HOH
W
120
−29.626
18.951
11.431
1.00
43.10
ATOM
3050
OW0
HOH
W
121
−14.313
21.458
−18.725
1.00
40.54
ATOM
3051
OW0
HOH
W
122
−0.759
26.600
1.740
1.00
45.86
ATOM
3052
OW0
HOH
W
123
−2.111
2.918
−16.154
1.00
46.67
ATOM
3053
OW0
HOH
W
124
3.331
26.748
−37.297
1.00
48.14
ATOM
3054
OW0
HOH
W
125
−2.436
28.999
−11.573
1.00
46.74
ATOM
3055
OW0
HOH
W
126
10.219
29.479
4.241
1.00
56.66
ATOM
3056
OW0
HOH
W
127
8.822
19.046
9.037
1.00
46.32
ATOM
3057
OW0
HOH
W
128
−2.874
16.046
4.626
1.00
37.70
ATOM
3058
OW0
HOH
W
129
−0.279
3.806
5.506
1.00
52.87
ATOM
3059
OW0
HOH
W
130
−32.360
19.413
1.195
1.00
50.24
ATOM
3060
OW0
HOH
W
131
−6.511
17.061
−7.831
1.00
39.09
ATOM
3061
OW0
HOH
W
132
2.417
23.144
8.408
1.00
44.56
ATOM
3062
OW0
HOH
W
133
−16.608
10.384
−12.085
1.00
45.07
ATOM
3063
OW0
HOH
W
134
−2.846
29.191
3.912
1.00
46.72
ATOM
3064
OW0
HOH
W
135
−17.527
21.749
4.420
1.00
43.90
ATOM
3065
OW0
HOH
W
136
−23.992
22.344
21.494
1.00
41.44
ATOM
3066
OW0
HOH
W
137
−23.795
27.206
3.547
1.00
54.65
ATOM
3067
OW0
HOH
W
138
−29.116
14.677
5.068
1.00
51.65
ATOM
3068
OW0
HOH
W
139
9.313
19.837
−4.271
1.00
55.48
ATOM
3069
OW0
HOH
W
140
−15.044
19.642
5.067
1.00
42.06
ATOM
3070
OW0
HOH
W
141
3.974
1.933
15.902
1.00
52.22
ATOM
3071
OW0
HOH
W
142
0.091
17.275
4.399
1.00
49.56
ATOM
3072
OW0
HOH
W
143
−25.537
21.936
14.509
1.00
42.90
ATOM
3073
OW0
HOH
W
144
−15.697
22.135
2.544
1.00
53.67
ATOM
3074
OW0
HOH
W
145
−16.772
39.732
17.788
1.00
46.17
ATOM
3075
OW0
HOH
W
146
−22.834
23.263
26.427
1.00
44.02
ATOM
3076
OW0
HOH
W
147
−4.433
30.459
1.897
1.00
54.37
ATOM
3077
OW0
HOH
W
148
10.805
29.216
−12.444
1.00
46.47
ATOM
3078
OW0
HOH
W
149
9.875
15.248
−22.074
1.00
39.59
ATOM
3079
OW0
HOH
W
150
19.274
21.111
10.902
1.00
45.24
ATOM
3080
OW0
HOH
W
151
−23.788
22.513
−8.738
1.00
50.90
ATOM
3081
OW0
HOH
W
152
−18.012
12.403
12.283
1.00
58.78
ATOM
3082
OW0
HOH
W
153
−23.602
19.922
19.962
1.00
46.19
ATOM
3083
OW0
HOH
W
154
19.294
22.358
13.809
1.00
47.46
ATOM
3084
OW0
HOH
W
155
−16.570
11.359
31.299
1.00
48.30
ATOM
3085
OW0
HOH
W
156
−10.846
16.772
31.754
1.00
51.00
ATOM
3086
OW0
HOH
W
157
−6.781
8.331
−29.531
1.00
48.71
ATOM
3087
OW0
HOH
W
158
−25.361
37.429
21.866
1.00
53.58
ATOM
3088
OW0
HOH
W
159
−25.833
29.686
21.358
1.00
50.75
ATOM
3089
OW0
HOH
W
160
−47.219
5.581
−4.792
1.00
56.63
ATOM
3090
OW0
HOH
W
161
6.673
27.621
−10.556
1.00
44.41
ATOM
3091
OW0
HOH
W
162
0.676
23.720
14.657
1.00
45.33
ATOM
3092
OW0
HOH
W
163
−17.977
1.385
−4.066
1.00
49.80
ATOM
3093
OW0
HOH
W
164
6.273
19.800
−5.128
1.00
41.05
ATOM
3094
OW0
HOH
W
165
1.774
1.455
12.183
1.00
53.13
ATOM
3095
OW0
HOH
W
166
−47.850
5.153
0.253
1.00
54.28
ATOM
3096
OW0
HOH
W
167
0.571
0.928
−8.183
1.00
57.03
ATOM
3097
OW0
HOH
W
168
−15.657
41.281
19.809
1.00
33.76
ATOM
3098
OW0
HOH
W
169
−1.350
19.580
18.894
1.00
48.90
ATOM
3099
OW0
HOH
W
170
−22.822
18.718
−8.056
1.00
46.46
ATOM
3100
OW0
HOH
W
171
−27.476
27.793
21.291
1.00
44.42
ATOM
3101
OW0
HOH
W
172
−13.995
8.378
13.827
1.00
46.07
ATOM
3102
OW0
HOH
W
173
1.334
4.996
−4.827
1.00
43.01
ATOM
3103
OW0
HOH
W
174
6.478
14.054
−35.398
1.00
65.54
ATOM
3104
OW0
HOH
W
175
−12.962
4.523
−16.881
1.00
54.38
ATOM
3105
OW0
HOH
W
176
8.991
14.162
−32.740
1.00
48.50
ATOM
3106
OW0
HOH
W
177
30.119
7.742
6.505
1.00
52.79
ATOM
3107
OW0
HOH
W
178
4.020
0.076
−9.889
1.00
58.79
ATOM
3108
OW0
HOH
W
179
1.144
5.559
−8.474
1.00
65.45
ATOM
3109
OW0
HOH
W
180
2.468
19.016
−2.946
1.00
58.33
ATOM
3110
OW0
HOH
W
181
8.790
31.553
−20.525
1.00
54.64
ATOM
3111
OW0
HOH
W
182
−2.088
20.162
20.999
1.00
50.34
ATOM
3112
OW0
HOH
W
183
−13.986
18.401
1.898
1.00
42.05
ATOM
3113
OW0
HOH
W
184
−12.269
28.571
−31.407
1.00
56.39
ATOM
3114
OW0
HOH
W
185
3.689
19.990
−5.623
1.00
51.48
ATOM
3115
OW0
HOH
W
186
−17.974
38.675
31.865
1.00
38.99
ATOM
3116
OW0
HOH
W
187
−19.158
28.362
36.510
1.00
54.63
ATOM
3117
OW0
HOH
W
188
−0.990
2.141
−5.489
1.00
52.92
ATOM
3118
OW0
HOH
W
189
−16.508
19.586
−9.105
1.00
39.50
ATOM
3119
OW0
HOH
W
190
−8.651
33.293
29.448
1.00
51.21
ATOM
3120
OW0
HOH
W
191
−21.074
18.375
−10.228
1.00
59.13
ATOM
3121
OW0
HOH
W
192
−6.961
2.168
−15.223
1.00
50.82
END
1.PublishNumber: US-2014308307-A1
2.Date Publish: 20141016
3.Inventor: MONTELIONE GAETANO T.
DAS KALYAN
ARNOLD EDWARD
MA LI-CHUNG
XIAO RONG
KRUG ROBERT M.
TWU KAREN Y.
KUO REI-LIN
4.Inventor Harmonized: MONTELIONE GAETANO T(US)
DAS KALYAN(US)
ARNOLD EDWARD(US)
MA LI-CHUNG(US)
XIAO RONG(US)
KRUG ROBERT M(US)
TWU KAREN Y(US)
KUO REI-LIN(TW)
5.Country: US
6.Claims:
(en)The present invention includes compositions and methods related to the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site on the surface of the influenza A non-structural protein 1 (NS1). Specifically, critical biochemical reagents, conditions for crystallization and NMR analysis, assays, and general processes are described for (i) discovering, designing, and optimizing small molecule inhibitors of influenza A (avian flu) viruses and (ii) creating attenuated influenza virus strains suitable for avian and human flu vaccine development.
7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. Ser. No. 13/907,472, filed on May 31, 2013, which is a divisional patent application of U.S. Ser. No. 12/706,804, filed on Feb. 17, 2010, now U.S. Pat. No. 8,455,621, which is a divisional of U.S. patent application Ser. No. 11/566,216, filed on Dec. 2, 2006, now U.S. Pat. No. 7,709,190, which claims priority to U.S. Provisional Application Ser. No. 60/741,764, filed Dec. 2, 2005 and Ser. No. 60/852,361 filed Oct. 16, 2006. All of the foregoing applications are hereby incorporated by reference in their entirety.
STATEMENT OF FEDERALLY FUNDED RESEARCH
This invention was made with U.S. Government support under Contract Nos. AI-11772 awarded by the NIH. The government has certain rights in this invention.
TECHNICAL FIELD OF THE INVENTION
The present invention relates in general to the field of anti-viral assays and molecules, and more particularly, to compositions and methods for developing, isolating and characterizing novel Influenza A virus inhibitors and vaccines.
INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC
The present application includes a TABLE filed electronically via EFS-Web that includes a file named NS1A_F2F3. The table was last modified Dec. 1, 2006 at 4:49 PM and includes 252,952 bytes.
TABLES
The patent application contains table(s) that have been included at the end of the specification.
BACKGROUND OF THE INVENTION
Without limiting the scope of the invention, its background is described in connection with Influenza virus.
Influenza A and B viruses cause a highly contagious respiratory disease in humans resulting in approximately 36,000 deaths in the United States annually (Wright and Webster, 2001; Prevention, 2005). These annual epidemics also have a large economic impact, and cause more than 100,000 hospitalizations per year in the United States alone. Influenza A viruses, which infect a wide number of avian and mammalian species, are responsible for the periodic widespread epidemics, or pandemics, that have caused high mortality rates (Wright and Webster, 2001). The most devastating pandemic occurred in 1918, which caused an estimated 20 to 40 million deaths worldwide (Reid et al., 2001). Less devastating pandemics occurred in 1957 and 1968. Influenza B virus infections comprise about 20% of the yearly cases, but influenza B virus, which appears to infect only humans, does not cause pandemics (Wright and Webster, 2001).
Influenza A and B viruses contain negative-stranded RNA genomes, which are in the form of eight RNA segments (Lamb and Krug, 2001). Most, but not all, of the corresponding genome RNA segments of influenza A and B viruses encode proteins of similar functions. Here we will focus on influenza A virus. The three largest genome segments encode the three subunits of the polymerase, PB1, PB2 and PA. The segment encoding PB1 also encodes a small nonstructural protein, PB1-F2, which has apoptotic functions. The middle-sized segments encode the hemagglutinin (HA), the nucleocapsid protein (NP) and the neuraminidase (NA). HA, the major surface protein of the virus, binds to sialic acid-containing receptors on host cells, and is the protein against which neutralizing antibodies are produced. NP protein molecules are bound at regular intervals along the entire length of each of the genomic RNAs to form ribonucleoproteins (RNPs), and also have essential functions in viral RNA replication. The NA viral surface protein removes sialic acid from glycoproteins. One of its major functions is to remove sialic acid during virus budding from the cell surface and from the HA and NA of the newly assembled virions, thereby obviating aggregation of the budding virions on the cell surface. The seventh genomic RNA segment encodes two proteins, M1 (matrix protein) and M2. The M1 protein underlies the viral lipid membrane, and is thought to interact with the genomic RNPs and with the inner (cytoplasmic) tails of the surface proteins, e.g., HA and NA. The M2 protein is an ion channel protein that is essential for the uncoating of the virus. The smallest segment encodes two proteins, NS1A and NS2. The NS2 protein mediates the export of newly synthesized viral RNPs from the nucleus to the cytoplasm. The NS1A protein is a multi-functional protein not that is not incorporated into virion particles (hence the designation “non structural”), and is discussed below.
The primary means for controlling influenza virus epidemics has been vaccination directed primarily against HA (Wright and Webster, 2001). However, the antigenic structure of the HA of influenza A virus can undergo two types of change (Wright and Webster, 2001). Antigenic drift results from the selection of mutant viruses that evade antibodies directed against the major antigenic type of the HA circulating in the human population. Mutant viruses are readily generated because the viral RNA polymerase has no proof-reading function. Because of antigenic drift, the vaccine has to be reformulated each year. Antigenic shift in HA results from reassortment of genomic RNA segments between human and avian influenza A virus strains, resulting in a new (potentially pandemic) virus encoding a novel avian-type HA that is immunologically distinct. The human population has little or no immunological protection against such a new virus. The viruses containing the H2 and H3 HA subtypes that caused pandemics in 1957 and 1968, respectively, resulted from the reassortment of avian and human genomic RNA segments (Wright and Webster, 2001). The HA of influenza B viruses undergoes antigenic drift, but not antigenic shift, because influenza B viruses do not have non-human hosts.
Pandemic influenza A viruses can also apparently arise by a different mechanism. It has been postulated that the 1918 H1 pandemic strain derived all eight genomic RNAs from an avian virus, and that this virus then underwent multiple mutations in the process of adapting to mammalian cells (Reid et al., 2004; Taubenberger et al., 2005). H5N1 viruses, which have already spread from Asia to Europe and Africa, appear to be undergoing this route for acquiring pandemic capability (Horimoto and Kawaoka, 2005; Noah and Krug, 2005). These viruses, which have been directly transmitted from chickens to humans, contain only avian genes, and are highly pathogenic in humans. The human mortality rate has been high, approximately 55% (WHO, 2006). H5N1 viruses have not yet acquired the ability for efficient transmission from humans to humans. Recent studies indicate that efficient human transmission will require more than the acquisition of the ability of HA to bind to human sialic acid receptors in the upper respiratory tract of mammalian organisms (Maines et al., 2006). However, at least one H5N1 gene, the PB2 gene, has already undergone adaptation to mammalian cells (Hatta et al., 2001). The vast majority of pathogenic H5N1 viruses have acquired a lysine at position 627 in the PB2 protein, in place of the glutamic acid that is found at this position in avian viruses. The presence of lysine at this position apparently enhances virus replication in mammalian cells, but the mechanism of enhancement has not been established (Crescenzo-Chaigne et al., 2002; Shinya et al., 2004).
Effective control of a H5N1 pandemic will require the use of antiviral drugs because it is not likely that sufficient amounts of an effective vaccine will be available, particularly in the early phase of a fast-spreading pandemic (Ferguson et al., 2005; Longini et al., 2005; Ferguson et al., 2006; Germann et al., 2006). Antivirals can be stockpiled, and if appropriately used, should limit the spread of pandemic influenza virus. The strategies that have been proposed for the use of antivirals to stem a H5N1 pandemic would also be expected to lead to more effective use of antivirals during annual influenza epidemics. Currently, there are two classes of antiviral drugs. One class, amantadine/rimantidine, is directed against the M2 ion channel of influenza A viruses (Pinto et al., 1992; Wang et al., 1993; Chizhmakov et al., 1996). Virus mutants resistant to this class of drugs rapidly emerge (Cox and Subbarao, 1999; Suzuki et al., 2003), and many of the human isolates of H5N1 viruses are already resistant to these drugs (Puthavathana et al., 2005). The other class of drugs is directed at NA, and is effective against both influenza A and B viruses (von Itzstein et al., 1993; Woods et al., 1993; Ryan et al., 1994; Gubareva et al., 1995; Kim et al., 1997; Mendel et al., 1998). However, H5N1 viruses that are partially, or completely, resistant to the NA inhibitor oseltamivir have been reported (de Jong et al., 2005; Le et al., 2005). The emergence of H5N1 viruses to these two classes of antiviral drugs highlights the need for additional antiviral drugs against influenza virus.
SUMMARY OF THE INVENTION
The present invention includes the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site, or “binding epitope”, on the surface of the influenza A non-structural protein 1 (NS1). When referring to influenza A, the protein is referred to herein as NS1A. The NS1 protein of influenza A virus will be designated as the NS1A protein to distinguish it from the NS1 protein encoded by influenza B virus, which will be designated as the NS1B protein. Several fragments of the NS1A protein were identified, from various influenza strains, that provide high-level expression and solubility in E. coli expression systems. The present invention also includes expression systems and protocols for producing large quantities of the previously identified F2F3 fragment of human CPSF30, which binds to the NS1A effector domain (Twu et al., 2006). These fragments of the NS1A protein and of CPSF30 provide high quality NMR spectra, suitable for lead compound optimization. Combining these reagents and information, we have designed a gel filtration assay suitable for characterizing complex formation between NS1A and CPSF30 (or fragments thereof), as well as a fluorescence polarization (FP) assay of NS1A-CPSF30 interactions that is suitable for high throughput screening for lead compounds to develop antiviral drugs. Using these reagents, complexes of the tetrameric complex between the NS1A effector domain and F2F3 were also generated. We have also developed a process for crystallizing this complex. These crystals were used to determine the 3D structure of the NS1A effector domain: F2F3 complex, and to definitively identify for the first time all the NS1A amino acids that comprise a portion of the CPSF30 binding epitope in the NS1A protein. These reagents and structural data, together with specific site-directed mutagenesis data, have allowed us to define a structure-based process for high-throughput screening of inhibitors and lead optimization that will allow development of influenza A antiviral drugs. Also disclosed is a process using these reagents and structural data to develop attenuated strains of influenza A suitable for use as animal (e.g. avian) or human vaccines.
Using the present invention it is possible for antiviral drug(s) to be directed at a viral target that differs from that of currently available influenza antivirals. Novel approaches are important because influenza A viruses, including avian influenza virus, are developing resistance to existing antiviral drugs. The present invention also describes a process for developing vaccines using structural information that has not been previously disclosed. A vaccine using live attenuated strains of influenza A virus is expected to provide better protection than a vaccine using inactivated virus. The present invention may also be used to develop, isolate and characterize antiviral drugs and live attenuated virus vaccine for both seasonal and pandemic influenza virus infections.
More particularly, the present invention includes a complex of the F2F3 fragment of CPSF30 with the portion of the NS 1A protein of influenza A virus comprising amino acid residues 85 to 215 (NS1A (85-215)). The complex can be used in a method of identifying an inhibitor of influenza A virus by preparing a reaction system comprising at least a portion of NS1A of an influenza A virus, the F2F3 fragment of CPSF30, and a candidate compound; and detecting binding between the at least a portion of NS1A and F2F3, wherein reduced binding in the presence of the candidate drug relative to the control is indicative of activity of the compound against influenza virus. Examples of the NS1A fragments are listed in Table 2, and may also include the full length NS1A, and mutations thereof. The skilled artisan will recognize that the NS1A protein fragment may be prepared from other strains of influenza A viruses, e.g., human influenza A virus, a bovine influenza A virus, an equine influenza A virus, a porcine influenza A virus, an avian influenza A virus, an avian H5N1 viral strain.
For use with the present invention, the CPSF30 may be, e.g., a full length CPSF30, F3 zinc-finger doman, an F2F3-F2F3 tandem duplex, an F1F2F3 fragment, a soluble fragment of CPSF30, combinations and mutants thereof. Detection of the binding may be by, e.g., a high throughput screening assay, X-ray crystallography, nuclear magnetic resonance, analytical gel filtration, and combinations thereof. Other methods of detecting the interaction of the NS1A and CPSF30 (or portions thereof) may be, e.g., fluorescence resonance energy transfer, fluorescence polarization, immunofluorescence, chemiluminescence, radioimmunoassays, enzyme linked immunosorbent assays, mass spectrometry, and combinations thereof. For example, fluorescence polarization may use either a fluorescent labeled CPSF30, variant or fragment thereof or a fluorescent labeled NS1A protein, variant or fragments thereof.
The present invention also includes a process for using 3D (three-dimensional) information of the CPSF30 binding epitope on the influenza A virus NS1A protein for identifying inhibitors of an influenza A virus by obtaining concurrently the coordinates for the molecular position of at least a portion of an influenza NS1A protein and at least a portion of a CPSF30 protein and designing a molecule that will fit between the influenza NS1A protein and the CPSF30 protein based on the coordinates. The portion of the NS1A protein and the portion of the CPSF30 protein will generally be selected to provide high quality NMR spectra, e.g., the NS1A (85-215) fragment and the F2F3 fragment may be selected to form a tetrameric complex.
In another example, the NS1A (85-215) fragment and the F2F3 fragment may form a tetrameric complex that is crystallized. Other examples may use an NS1A (85-215) fragment and the F2F3 fragment form a tetrameric complex that is crystallized and is used to determine the 3D structure of the NS1A (85-215):F2F3 complex using X-ray crystallography. The method may also include the step of identifying the NS1A amino acids that constitute the CPSF30 binding portion of the NS1A protein.
Yet another embodiment is a method of designing an inhibitor compound of an influenza A virus based on computational methods, wherein the inhibitor that binds at least one residue within the set of residues corresponds to the structure, using the crystal structure and its coordinates. The design method may be facilitated by using NMR spectra of samples of NS1A protein fragments, NMR spectra of samples of NS1A(85-215) or equivalent constructs thereof. The method may further include the step of optimizing the design of the molecule that fits between the NS1A (85-215) protein and the CPSF30 protein using X-ray crystallography, and synthetic chemistry. The method of designing an inhibitor compound may also include the step of optimizing the design of the molecule that fits between the NS1A(85-215) protein and the CPSF30 protein using X-ray crystallography, NMR, synthetic chemistry and combinations thereof. Another embodiment of method of designing an inhibitor compound may also include, optionally or in combination one or more of the following: modifying the F2F3 structure of CPSF30, or any substructure, based on its conformation bound to NS1A to rationally design one or more small molecule inhibitors; modifying the F2F3 structure of CPSF30, or any substructure, to rationally design one or more small molecule inhibitors based on its conformation bound to NS1A of the F2F3 aromatic rings, the sidechain of residue Lys101, or combinations thereof; modifying the F2F3 structure of CPSF30, or any substructure, to rationally design one or more small molecule inhibitors by virtual screening; using the three-dimensional structure of the NS1A binding pocket to select one or more small molecule inhibitors or using the three-dimensional structure of the NS1A binding pocket to select one or more small molecule inhibitors by virtual screening. Any fragments of, full length, and strains of NS1A, and fragments of, full length, and strains of CPSF30 and combinations thereof may be used in conjunction with the method of designing an inhibitor compound.
Another embodiment of the present invention includes a process for engineering a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interface and combinations thereof. Specific examples of residues at the tetramer interface site include, e.g., F103, L105, M106 and equivalents thereof. Specific examples of residues at the CPSF30-binding epitope include, e.g., M106, K110, 1117, 1119, Q121, D125, V180, G183, G184, W187 and equivalents thereof. The process may further include mutating the double-strand RNA binding epitope.
Another embodiment of the present invention includes an attenuated influenza A virus vaccine that includes one or more of eight viral RNA segments, wherein a viral RNA segment eight has a first mutation that causes a substitution of a first amino acid corresponding to an amino acid of SEQ. ID. NO. 1 at a position F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, or W187; wherein the first mutation decreases the CPSF30 binding ability of the NS1A protein. In one embodiment, at least a second mutation anywhere in the NS1A protein. The vaccine may also include at least second mutation causes a substitution of at least a second amino acid corresponding to an amino acid of SEQ ID NO.: 1 at a position F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, W187 and equivalents thereof. Alternatively, the vaccine may also include at least second mutation with a substitution of at least a second amino acid corresponding to an amino acid of SEQ ID NO.: 1 at a position T5, P31, D34, R35, R38, K41, G45, R46, and T49 at a dsRNA binding epitope and equivalents thereof. Alternatively, the vaccine may also include at least second mutation with at least second mutation causes a substitution of at least a second and third amino acid corresponding to an amino acid of SEQ. ID. NO. 1 at a position T5, P31, D34, R35, R38, K41, G45, R46, and T49 at a dsRNA binding epitope and/or F103, L105, M106, K110, 1117, 1119, Q121, D125, L144, V180, G183, G184, W187 and equivalents thereof. The influenza virus is a may be a cold-adapted influenza virus and will generally be selected to elicit an immune response. Non-limiting examples of influenza virus that may be used to make the attenuated vaccine may be is selected from, e.g., a human influenza A virus, a bovine influenza A virus, an equine influenza A virus, a porcine influenza A virus, an avian influenza A virus, an avian H5N1 viral strain.
The present invention also includes a pharmaceutical composition having a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS 1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interaction site and combinations thereof and a pharmaceutically acceptable carrier or diluent. The vaccine may be used in a method of prophylaxis of a disease condition caused by the influenza virus by administering to a subject in need thereof a therapeutically effective amount of a live attenuated influenza A virus vaccine by mutation of specific residues in the CPSF30-binding epitope of the NS1A protein based on the 3D structure of the complex formed between NS1A (85-215) and F2F3, a tetramer interaction site, the dsRNA binding epitope and combinations thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:
FIGS. 1A and 1B are graphs that show the effects on the growth of a recombinant influenza A virus resulting from mutations in its of mutations on NS1A protein that relate to the ability of the NS1A to bind to CPSF30;
FIG. 2 shows NMR spectra of certain NS1A effector domains, demonstrating that such data can be used for structure-function analysis, inhibitor discovery and optimization, and in validating the effects of mutations on the structure of the effector domain;
FIG. 3 shows the results from analytical gel filtrations assays of NS1A (85-215):F3F3 binding;
FIG. 4A shows the X-ray crystal structure of a tetrameric NS1A effector domain and F2F3;
FIG. 4B shows the X-ray crystal structure for the Met106 residue in the core of the tetrameric NS1A (85-215):F2F3 complex;
FIG. 5 shows the X-ray crystal structure for the F2F3 binding epitope on the surface of the NS1A effector domain;
FIG. 6 is a comparison of 3D structures for Udorn and PR8 NS1A effector domains; and
FIG. 7 shows the 3D structure and dimeric beta-sheet interface of the PR8 effector domain, which does not bind F2F3.
DETAILED DESCRIPTION OF THE INVENTION
While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
One of the best clues to a protein's function is its structure. The present invention takes advantage of structure-based bioinformatics platforms in “functional genomics.” The structure-function data obtained from various structural determination may be used the isolation of novel biopharmaceuticals and/or drug targets from gene sequence information with greater efficiency. One way to identify the biochemical and medical function of a gene product is to determine its three-dimensional structure. Although there are numerous examples in which the primary (i.e., linear) structure of a protein has provided key clues to its biochemical function, three dimensional (3D) structure determination is considered to be more definitive at establishing biochemical function and mechanisms underlying these functions.
Protein structure. It is a generally accepted principle of biology that a protein's primary sequence is the main determinant of its tertiary structure. Anfinsen, Science 181:223-230 (1973); Anfinsen and Scheraga, Adv. Prot. Chem. 29:205-300 (1975); and Baldwin, Ann. Rev. Biochem. 44:453-475 (1975). For over a decade, researchers have been studying the theoretical and practical aspects of the folding of recombinant proteins.
Generally, proteins are composed of one or more autonomously-folding units known as domains. Kim, et al., Ann. Rev Biochem. 59:631-660 (1990); Nilsson, et al., Ann. Rev. Microbiol. 45:607-635 (1991). Multi-domain proteins in higher organisms are encoded by genes containing multiple exons and combinatorial shuffling of exons during evolution has produced novel proteins with different domain arrangements having different associated functions. Multi-domain protein may increase the ability of higher organisms to respond to environmental challenges because, via recombinational events, because the genomes may readily add, subtract, or rearrange discrete functionalities within a given protein. Patthy, Cell 41:657-663 (1985); Patthy, Curr. Opin. Struct. Bio. 4:383-392 (1994); and Long, et al., Science 92:12495-12499 (1995).
Interpretation of a protein structure. Several methods have been used to elucidate the 3D structure of a given protein molecule, e.g., X-ray crystallography and Nuclear Magnetic Resonance (NMR).
X-ray crystallography. X-ray crystallography is a technique that directly images molecules. A crystal of the molecule to be visualized is exposed to a collimated beam of monochromatic X-rays and the consequent diffraction pattern is recorded on a photographic film or by a radiation counter. The intensities of the diffraction maxima are then used to construct mathematically the three-dimensional image of the crystal structure. X-rays interact almost exclusively with the electrons in the matter and not the nuclei. The spacing of atoms in a crystal lattice can be determined by measuring the angle and intensities at which a beam of X-rays of a given wave length is diffracted by the electron shells surrounding the atoms. Operationally, there are several steps in X-ray structural analysis. The amount of information obtained depends on the degree of structural order in the sample. Blundell et al. provide an advanced treatment of the principles of protein X-ray crystallography. Blundell, et al., Protein Crystallography, Academic Press (1976), herein incorporated by reference. Likewise, Wyckoff et al. provide a series of articles on the theory and practice of X-ray crystallography. Wyckoff, et al. (Eds.), Methods Enzymol. 114: 330-386 (1985), relevant portions herein incorporated by reference. Important techniques for X-ray crystallography include methods for determining diffraction data phases by a multiple anomalous dispersion (MAD) method (described, for example, in Hendrickson, 1991), particularly using biosynthethic enrichment with seleno-methione (SeMet), and a molecular replacement method (described, for example, in Rossmann, M. G. The molecular replacement method. Acta Cryst. A46, 73-82 (1990).
Nuclear Magnetic Resonance (NMR). A general approach for the analysis of NMR resonance assignments was first outlined by Wuthrich, Wagner and co-workers. Wuthrich, “NMR of proteins and nucleic acids” Wiley, New York, New York (1986); Wuthrich, Science 243:45-50 (1989); Billeter, et al., J. Mol Biol. 155:321-346 (1982), relevant portions of each incorporated herein by reference. For a general review of protein determination in solution by nuclear magnetic resonance spectroscopy, see Wuthrich, Science 243:45-50 (1989); Billeter et al., J. Mol. Biol. 155:321-346 (1982). More recent improvements using multidimensional and triple resonance NMR methods (described, for example, in J. Cavanagh, W. Fairbrother, A. Palmer, and N. Skelton, Protein NMR Specroscopy, Principles and Practice, 2ed Ed, Academic Press, N.Y., 2006, incorporated herein), familiar to someone trained in the art, are elaborations of these basic principles.
As used herein, the terms “CPSF30 binding epitope” or “CPSF binding site” refer to that portion of the NS1 protein of influenza that interacts with one or more zinc fingers of the CPSF30 protein.
As used herein, the terms “NS1A-binding epitope” or “NS1A binding site” refer to that portion of the CPSF30 protein that interacts with the NS1 protein of influenza A.
As used herein, the term “tetramer interface” refers to those portions of the NS1A protein and the CSPF30 protein that interact NS1A:CPSF30 complex, which can be a dimer or tetramer.
As used herein, the terms “double-strand RNA binding site” or “doubled-stranded RNA binding epitope” refer to that portion of the NS1A protein that interacts with double-stranded RNA, e.g., for suppressing host innate immune response. Greater structural details regarding the double-strand RNA binding site is taught by the present co-inventors in PCT/US2003/036,292, “Process for Designing Inhibitors of Influenza Virus Non-Structural Protein 1,” relevant portions incorporated herein by reference and U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference.
As used herein, the term “epitope” refers to a portion of a protein that is capable of interacting with the same or another protein and that can be define by atoms in amino acids in a linear sequence, by atoms in amino acids that are located throughout the protein (or subunits thereof) and that come together in three dimensions to form an interactive structure. The skilled artisan will recognize that an epitope may be a structure such as a “zinc finger,” a portion of a molecular surface between two or more polypeptides that are capable of interacting, and/or a “binding pocket” or “enzymatic pocket” that lead to a function or interaction of the protein.
As used herein, the following nomenclature is used to define the zinc finger domains of the CPSF30 protein that interact NS1A, namely, “F1”, “F2” and “F3” when referring to individual zinc fingers, “F1F2”, “F2F3” when referring to a pair of zinc fingers and “F1F2F3” when referring to the three zinc fingers.
As used herein, the term “rationally design” refers to a series of steps for designing, e.g., initial small molecule inhibitors that may be further refined through medicinal chemistry and/or the selection of inhibitors that can be further modified chemically and that fit the molecular characteristics of a molecule that will meet the design criteria for modifying the interactions between or the activity of NS1A and CPSF30 based fully and/or at least in part on the three dimensional (3D) coordinates described herein.
As used herein, the term “virtual screening” refers to in silico design, using computer software to screen for possible binding ligands from a library of virtual molecules, allowing the characterization and refinement of small molecule inhibitors that will meet the design criteria for modifying the interactions between or the activity of NS1A and CPSF30 based fully and/or at least in part on the three dimensional (3D) coordinates described herein.
As used herein, the term “corresponding positions” refers to amino acids at that are generally in the same spatial location in the three-dimensional structures of homologous protein structures. In one example, a corresponding position is determined by 3D structure alignment using standard techniques known to a person skilled in the art, such as the PRISM program, described by Yang and Hong Yang, A.-S. and Honig, B. (2000) An Integrated Approach to the Analysis of Sequence and Structure. I. Protein Structural Alignment and a Quantitative Measure for Protein Structural Distance. J. Mol. Biol. 301: 665-678; Yang, A.-S. and Honig, B. (2000) An Integrated Approach to the Analysis of Sequence and Structure. III. A Comparative Study of Sequence Conservation in Protein Structural Families Using Multiple Structural Alignments, or the VISTAL program, described by Kolodny, R. and Honig, B. (2006) VISTAL—A New 2D Visualization Tool of Protein 3D Structural Alignments. Bioinformatics 22:2166-2167 (e.g., using the default settings for either), relevant portions incorporated herein by reference. The alignment may include the introduction of gaps in the sequences to be aligned. In the absence of 3D structures for protein pairs, corresponding positions may be identified (until such time that the requisite 3D structures are available) by sequence-based alignment using stardard techniques known to a person skilled in the art, such as a Needleman-Wunsch dynamic programming algorithm (described in Needleman, S. B. and Wunsch, C. D., J Mol Biol. 48: 443-453 (1970), a Gapped BLAST/PSI-BLAST algorithm (described in Altschul, et al Nucl. Acid. Res. 25: 3389-3402 (1997), or a CLUSTAL W/X multiple sequence alignment algoithm (described in Thompson, J. D., Higgins, D. G. and Gibson, T. J. (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position specific gap penalties and weight matrix choice. Nucl. Acid. Res. 22:4673-80 (1994).)(e.g., using the default settings for either relevant portions incorporated herein by reference. Corresponding position alignment(s) may also include the introduction of gaps in the sequences to be aligned.
Further examples of “corresponding positions are taught by the present co-inventors in PCT/US2003/036,292, “Process for Designing Inhibitors of Influenza Virus Non-Structural Protein 1,” relevant portions incorporated herein by reference and U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections”, and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference.
Non-limiting examples of numerous influenza A strains may be used with the present invention including those strains that are readily available or will become available as they emerge in human populations. Examples of influenza A strains for use and analysis with the present invention may include A/Memphis/8/88, A/Chile/1/83, A/Kiev/59/79, A/Udorn/307/72, A/NT/60/68, A/Korea/426/68, A/Great Lakes/0389/65, A/Ann Arbor/6/60, A/Leningrad/13/57, A/Singapore/1/57, A/PR/8/34, A/Vietnam/1203/04, A/HK/483/97, A/South Carolina/1/181918 (the 1918 pandemic virus H1N1 strain), and A/WSN/33. The sequences of these strains are available from GenBank, CDC and viral stock may be available from the American Type Culture Collection, Rockville, Md. or are otherwise publicly available.
As used herein, the term “variant” gene or protein refers to a gene or protein that differs from the wild type gene or protein by way of nucleotide or amino acid substitution(s), addition(s), deletion(s), and combinations thereof. Depending on the context, the term mutant is also used to describe variations from the wild-type sequence that are natural, introduced at random and/or introduced into a gene or protein sequence specifically. Likewise, a fragment is used to describe a fragment of the complete length of the translated polypeptide, whether natural or not. Often, the skilled artisan will design fragments that include or avoid certain amino acid that may affect, e.g., synthesis or cause steric hindrance or other design requirements. When designing alternate peptide constructs with enhanced anti-viral properties, substitutions may be used which modulate one or more properties of the molecule. Variants typically include the exchange of one amino acid for another at one or more sites within the peptide. For example, certain amino acids may be substituted for other amino acids in a peptide structure in order to enhance the interactive binding capacity of the structures. Certain amino acid substitutions can be made in a protein sequence (or its underlying DNA coding sequence) to create a peptide with superior functional characteristics. In particular, those changes that enhance the amphipathic, α-helical nature may be desired.
As used herein, the term “candidate compound” refers to any molecule that may inhibit influenza viral growth. The candidate substance may be a protein or fragment thereof, a small molecule, or even a nucleic acid molecule. Various commercial sources of small molecule libraries meet the basic criteria for useful drugs in an effort to “brute force” the identification of useful candidate compounds. Screening of such libraries, including libraries generated combinatorially (e.g., peptide libraries, aptamer libraries, small molecule libraries), is a rapid and efficient way to screen large number of related (and unrelated) compounds for activity. Combinatorial approaches also lend themselves to rapid evolution of potential drugs by the creation of second, third and fourth generation compounds modeled of active, but otherwise undesirable compounds. Candidate compounds may be screened from large libraries of synthetic or natural compounds. One example of a candidate compound library is an FDA-approved library of compounds that can be used by humans. Synthetic compound libraries are commercially available from a number of companies including Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.), and Microsource (New Milford, Conn.) and a rare chemical library is available from Aldrich (Milwaukee, Wis.). Combinatorial libraries are available or can be prepared. Alternatively, libraries of natural candidate compounds in the form of bacterial, fungal, plant and animal extracts are also available from, for example, Pan Laboratories (Bothell, Wash.) or MycoSearch (N.C.), or can be readily prepared by methods well known in the art. Candidate compounds isolated from natural sources, such as animals, bacteria, fungi, plant sources, including leaves and bark, and marine samples may be assayed as candidates for the presence of potentially useful pharmaceutical agents. It will be understood that the pharmaceutical agents to be screened could also be derived or synthesized from chemical compositions or man-made compounds.
The amino acid sequence of the NS1A protein of Influenza A virus, A/Udorn/72:
(SEQ ID NO.: 1)
1
MDPNTVSSFQ VDCFLWHVRK RVADQELGDA PFLDRLRRDQ
KSLRGRGSTL GLDIETATRA
61
GKQIVERILK EESDEALKMT MASVPASRYL TDMTLEEMSR
EWSMLIPKQK VAGPLCIRMD
121
QAIMDKNIIL KANFSVIFDR LETLILLRAF TEEGAIVGEI
SPLPSLPGHT AEDVKNAVGV
181
LIGGLEWNDN TVRVSETLQR FAWRSSNENG RPPLTPKQKR
EMAGTIRSEV.
The anti-viral agents disclosed herein may be used in conjunction with methods to reduce virus growth, infectivity, burden, shed, development of anti-viral resistance, and to enhance the efficacy of traditional anti-viral therapies.
The amino acid sequence of the relevant fragments of human CPSF30 (UniProt id 095639):
(SEQ ID NO.: 13)
1
MQEIIASVDH IKFDLEIAVE QQLGAQPLPF
50
PGMDKSGAAV CEFFLKAACG
51
KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD
100
QCEFLHEYDM TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK IKDCPWYDRG
150
FCKHGPLCRH RHTRRVICVN
151
YLVGFCPEGP SCKFMHPRFE LPMGTTEQPP
200
LPQQTQPPAK QSNNPPLQRS
201
SSLIQLTSQN SSPNQQRTPQ VIGVMQSQNS
250
SAGNRGPRPL EQVTCYKCGE
251
KGHYANRCTK GHLAFLSGQ
The amino acid sequence of the relevant fragments of human CPSF30 discussed in this patent are:
F1 Zn-Finger Domain: residues 41-59;
F2 Zn-Finger Domain: residues 68-86;
F3 Zn-Finger Domain: residues 96-114;
F4 Zn-Finger Domain: residues 124-142;
F5 Zn-Finger Domain: residues 148-166; and
F5 Zn-Finger Domain: residues 243-260.
As used herein F2F2 are residues 61-121 of SEQ ID NO.: 13:
61
SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM
100
TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK I
121
As used herein F1F2F3 are residues 39-121 of SEQ ID NO.: 13:
39
AV CEFFLKAACG
50
51
KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD
100
QCEFLHEYDM TKMPECYFYS
101
KFGECSNKEC PFLHIDPESK
121
The anti-viral properties of the peptides disclosed herein allow them to be included in formulations to inhibit virus growth and proliferation. The purified anti-viral peptides may be used without further modifications or they may be diluted in a pharmaceutically acceptable carrier. The invention may be administered to humans or animals, included in food and pharmaceutical preparations. They anti-viral agents may also be used in medicinal and pharmaceutical products (such as fluid containers, iv. bags, tubing, syringes, etc.), as well as in cosmetic products, hygienic products, cleaning products and cleaning agents, as well as any material to which the peptides could be sprayed on or adhered to wherein the inhibition of virucidal growth on such a material is desired.
The dosage of an anti-viral peptide necessary to prevent viral growth and proliferation depends upon a number of factors including the types of virus that might be present, the environment into which the peptide is being introduced, and the time that the peptide is envisioned to remain in a given area.
As used herein, the phrases “pharmaceutically” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well know in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
The active antiviral agents of the present invention may be formulated into classic pharmaceutical preparations and administered via any common route so long as the target tissue is available via that route. These routes of administration include, e.g., oral, alveolar, nasal, buccal, rectal, vaginal or topical. In particular, use of the anti-viral peptides of the present invention in a condom or diaphragm, optionally in conjunction with a spermicidal or other contraceptive substance, is envisioned. Alternatively, administration may be orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous. The antiviral agent may also be administered parenterally or intraperitoneally. Solutions of the antiviral agent may be compounded into a free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The antiviral agent(s) will generally be provided in a pharmaceutical dosage form suitable for injectable use, e.g., sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For widespread use, the antiviral agents may be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The antiviral agents will commonly be provided with a carrier, e.g., a solvent or dispersion medium that may include, e.g., water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper dosage fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and/or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, the dosage form will include isotonic agents, e.g., sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Generally, sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that includes the basic dispersion medium and the required other ingredients from those enumerated above. Preparation of sterile powders for injectable solutions maybe prepared by, e.g., vacuum-drying, spray-freezing, freeze-drying or other techniques that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
As used herein, a “pharmaceutically acceptable carrier” refers to solvents, dispersion media, coatings, antibacterial and anti-fungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
For oral administration, the antiviral agent(s) of the present invention may be incorporated with excipients and used in the form of ingestible or non-ingestible mouthwashes and dentifrices. A mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution). Alternatively, the antiviral agent(s) may be incorporated into an antiseptic wash containing sodium borate, glycerin and potassium bicarbonate. The antiviral agent(s) may also be dispersed in dentifrices, e.g., gels, pastes, powders and slurries. The antiviral agent(s) may be added in a therapeutically effective amount to a paste dentifrice that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
The antiviral agent(s) may be formulated in a neutral or salt form. Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric and the like. Salts may also be formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
Upon formulation, the antiviral agent(s) will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like. Sterile aqueous media that can be employed will be known to those of skill in the art in light of the present disclosure, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), relevant portions incorporated herein by reference. Some variation in dosage will necessarily occur depending on the condition of the subject being treated for which the skilled artisan will determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologics standards.
In one embodiment, the vaccine comprises a pharmaceutically acceptable vehicle. The suitable vehicles may be both aqueous and non-aqueous. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption. Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, immunostimulats, immunosuppressants, wetting agents, emulsifying and suspending agents, or any combination thereof.
Examples of suitable adjuvants include, without limitation, incomplete Freund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum, Stimulon® QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.), MPL® (3-0-deacylated monophosphoryl lipid A; Corixa, Hamilton, Mont.), and interleukin-12 (Genetics Institute, Cambridge, Mass.).
A person of the ordinary skill in the art has a sufficient expertise to determine the dosage of the vaccines of the instant invention. Such dosage depends on the pathogenicity of the virus included in the vaccine and on the ability of the antigen to elicit an appropriate immune response. In different embodiments of the invention, a virus vaccine composition of the instant invention may comprise from about 10 2 -10 9 plaque forming units (PFU)/ml, or any range or value therein (e.g., 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , or 10 8 ) where the virus is attenuated. A vaccine composition comprising an inactivated virus can comprise an amount of virus corresponding to about 0.1 to 200 μg of the amino acid sequences of the instant invention per ml, or any range or value therein.
The vaccines of the instant invention can be applied in multiple ways. According to one embodiment of the invention, the intranasal administration is via the mucosal route. The intranasal administration of the vaccine composition can be formulated, for example, in liquid form such as, for example, nose drops, spray, or suitable for inhalation. In other embodiment, the vaccine may be administered as a powder, or a cream, or an emulsion.
In another embodiment, the vaccines of the instant invention are applied by an injection, including, without limitation, intradermal, transdermal, intramuscular, intraperitoneal and intravenous. According to another embodiment of the invention, the administration is oral and the vaccine may be presented, for example, in the form of a tablet or encased in a gelatin capsule or a microcapsule, which simplifies oral application. The production of these forms of administration is within the general knowledge of a technical expert.
As used herein, “detectable labels” refer to compounds and/or elements that can be detected due to their specific functional properties and/or chemical characteristics, the use of which allows the agent to which they are attached to be detected, and/or further quantified if desired, such as, e.g., an enzyme, an antibody, a linker, a radioisotope, an electron dense particle, a magnetic particle or a chromophore. The detectable label may be half of a fluorescence resonance energy transfer (FRET) pair (for FRET variations see, e.g., U.S. Pat. No. 6,593,091, issued to Keys, relevant portions incorporated herein by reference). There are many types of detectable labels, including fluorescent labels, which are easily handled, inexpensive and nontoxic. Another example of a detection method relies on hydrogel-coated donor and acceptor beads providing functional groups for conjugation to biomolecules. AlphaScreen® by Berthold Technologies (Bad Wildbad, Germany)(Rouleau, N., Turcotte, S., Mondou, M. H., Roby, P. & Bosse, R. (2003) J Biomol Screen 8, 191-7.).
The present inventors recognized that certain regions of the NS1A protein can be targeted for the development of antiviral drugs. The NS1A protein is a multi-functional dimeric protein that participates in both protein-RNA and protein-protein interactions (Krug et al., 2003). The effector domain, which comprises the C-terminal two-thirds of the NS1A protein, contains the binding site for the 30-kDa subunit of the cellular cleavage and polyadenylation specificity factor (CPSF30) (Nemeroff et al., 1998; Li et al., 2001). This interaction results in the inhibition of 3′ end processing of all cellular pre-mRNAs in infected cells, and as a consequence the production of mature mRNAs encoding antiviral proteins (such as interferon, IFN) is severely inhibited during infection (Shimizu et al., 1999; Kim et al., 2002; Noah et al., 2003). This inhibition is crucial to viral replication and spread, because influenza A virus, like several other RNA viruses (Yoneyama et al., 2004; Sumpter et al., 2005; Seth et al., 2006), efficiently activates the RIG-I RNA helicase and thereby triggers both the activation of IRF-3 and NF-kB and the synthesis of IFN-beta and other antiviral pre-mRNAs (Geiss et al., 2002; Kim et al., 2002; Siren et al., 2006). A recombinant influenza A/Udorn/72 virus expressing a NS1A protein with a mutated binding epitope for CPSF30 induced high levels of IFN-beta mRNA during infection and was highly attenuated (100-1000-fold) (Noah et al., 2003; Twu et al., 2006). A 61-amino-acid domain of CPSF30, comprising two of its zinc fingers (i.e., the F2F3 fragment), was found to bind efficiently to the NS1A protein (Twu et al., 2006). The expression of the F2F3 domain in cells leads to the inhibition of influenza A virus replication and increased production of IFN-beta mRNA, indicating that F2F3 likely blocks the binding of endogenous CPSF30 to the NS1A protein (Twu et al., 2006). These results validate the binding epitope on NS1A for CPSF30 as a potential target for the development of small molecule antiviral drugs directed against influenza A virus and as a target for engineering strains of virus that can be used as live attenuated vaccines.
Previous studies showed that residues 184-188 in the protein sequence of the NS1A protein are required for functional binding of CPSF30 (Li et al., 2001; Noah et al., 2003). Thus, this region is required for the binding of CPSF30 in vitro (Li et al., 2001), and mutation of amino acids 184-188 in the NS1A protein of a recombinant Udorn virus results in high attenuation coupled with increased synthesis of IFN-beta (Noah et al., 2003). These data demonstrate that this binding epitope is essential for virus replication. As shown by the structural studies described below, the 184-188 region of the NS1A protein sequence constitutes a subset of the CPSF30 binding epitope, observed in the 3D structure of the complex between NS1A effector domain and F2F3 which is disclosed for the first time in this Disclosure.
Studies with the NS1A proteins of H5N1 viruses established that the Met (M) residue at position 106 is required for functional F2F3/CPSF30 binding. We showed that the NS1A protein encoded by a pathogenic H5N1 virus that was transmitted to humans in 1997 (A/HK/483/97; HK97) lacks a binding epitope for CPSF30, whereas the NS1A protein encoded by a pathogenic 2004 H5N1 virus (A/Vietnam/1203/04; VN04) has acquired this binding epitope. We were able to generate a CPSF30 binding epitope in the HK97 NS1A protein by changing two of its amino acids to the corresponding amino acids in the VN04 NS1A protein, specifically by changing I at position 106 to M and L at 103 to F. To determine the effects of these two amino acid changes in the HK97 NS 1A protein during virus infection, a recombinant Udorn virus was generated in which the Udom NS gene was replaced by a HK97 NS gene encoding a NS1A protein with these two mutations (Ud/dmHK97 recombinant). The recombinant virus was then compared to the recombinant Ud virus containing the wild-type HK97 NS gene (Ud/HK97 recombinant). During multiple cycle growth the rate of replication and virus yield of the Ud/dmHK97 recombinant was 100-fold greater than with the Ud/HK97 recombinant virus ( FIG. 1A ), and is thus similar to the Udorn parent virus. During single-cycle growth, the Ud/HK97 virus induced a high level of IFN-beta mRNA production, which was almost completely suppressed in the cells infected by the Ud/dmHK97 virus ( FIG. 1B ). Most importantly, the replication of the Ud/dmHK97 virus was inhibited in F2F3-expressing cells (data not shown), indicating that the dmHK97 NS1A protein binds F2F3 in infected cells. The roles of Phe at 103 and the Met at 106 in the NS1A protein in forming the F2F3/CPSF30 complex is elucidated by the herein disclosed X-ray crystal structure of the NS1A:F2F3 complex, which reveals that amino acids 103 and 106 are required for CPSF30 binding because their hydrophobic interactions stabilize a tetrameric structure of the NS1A:F2F3 complex (see below). It should also be emphasized that essentially all (>98%) of the influenza A viruses (H3N2, H2N2 and H1N1) that have been isolated from humans, including the 1918 H1N1 virus, and include M and F at positions 106 and 103 in their NS1A proteins, respectively, indicating that these two amino acids, which are critical for CPSF30 binding and the resulting suppression of the production of IFN-β mRNA, are conserved in human influenza A viruses. Accordingly, the tetrameric complex described in this disclosure is anticipated to be critical for the CSPF30 binding function of all such human influenza A viruses.
EXAMPLE 1
Process for Discovering, Designing, and Optimizing Small Molecule Inhibitors of Influenza A Viruses, Including H5N1 Viruses
Novel Reagents and Structural Data. To further delineate the interface between F2F3 of CPSF30 and the NS1A protein the inventors determined the three-dimensional (3D) structure of the tetrameric F2F3:NS1A complex. Ninety (90) different constructs (Table 2) were screened in order to find constructs suitable for crystallization and NMR analysis. These variants, summarized in Tables 3 and 4, included 8-11 different full-length or subsequences of NS1A with N-terminal (N-His) and C-terminal (C-His) affinity purification tags, prepared as described in Acton et al., 2005 from influenza A strains A/South Carolina/1/181918 (the 1918 pandemic virusH1N1 strain), HK97 (A/HK/483/97, 1997 Hong Kong), VN04 (A/Vietnam/1203/04, 2005 Vietnam), and Udom (A/Udorn/72), respectively. These were assessed in terms of expression level and solubility (Tables 3 and 4), ability to purify, and biophysical properties, including 2D 15 N- 1 H heteronuclear single quantum coherence correlation spectroscopy (HSQC). Many of these reagents, disclosed for the first time here, are useful for influenza A research purposes and for structural studies. The inventors focused on two specific constructs that provide particularly high expression and solubility, making them especially useful for biochemical and biophysical studies: the C-terminal hexaHis-tagged 85-215 amino acid fragments of the NS1A proteins from (i) influenza A/Udorn/72 (A/Udom) and (ii) the H5N1 strain A/Vietnam/1203/04 (A/VN04). These highly soluble constructs can be produced in tens of milligram per liter quantities, and have been produced with SeMet labeling, for crystallography, and with 15 N-enrichment for NMR studies. Excellent quality HSQC NMR spectra can be obtained for these two constructs in the pH range 5.5 to 6.5 ( FIG. 2 ). Under these conditions, these constructs are of sufficiently good quality to indicate high feasibility for further NMR studies. They are also useful for small molecule screening studies. In addition, the F2F3 fragment of CPSF30 has been cloned into a pET expression vector with a N-terminal hexaHis tag (tag sequences are defined in Acton et al., 2005), produced with uniform 13 C, 15 N enrichment, and complete backbone and sidechain resonance assignments have been determined using standard triple resonance NMR methods (Montelione et al., 1999). These NMR-optimized sample conditions and resonance assignments are useful for small molecule screening, lead optimization, and structure-function studies of F2F3:NS1A interactions.
Because virus studies have used influenza A/Udorn/72 virus to identify CPSF30 binding activity during virus infection CPSF30 (Li et al., 2001; Noah et al., 2003), we have developed an assay for the binding of the NS1A Udorn effector domain to the F2F3 fragment of CPSF30 in vitro, using analytical gel filtration with detection of effluent by simultaneous refractive index and static light scattering measurements. The chromatography system used for this assay is described in Acton et al., 2005, in which it is used for other applications. In these studies, illustrated in FIG. 3 , the NS1A Udorn (85-215) construct elutes as a dimer, with molecular weight of ˜30 kDa. When this effector domain construct is first mixed with the 8.5 kDa F3F3 fragment, the resulting complex elutes with a molecular weight of ˜50 kDa, indicating a stoichiometry of 2 F2F3:2 NS1A effector domains. This gel filtration assay provides a convenient qualitative measure of F2F3 binding by NS1A effector domains.
Suitable samples of NS1A Udorn (85-215); the NS1A-Udorn(85-215):F2F3 complex, and other constructs listed in Table 2 and their complexes with F2F3 and CPSF30-derived constructs, can be produced and assessed using this gel filtration assay. These can then be crystallized for X-ray crystallographic analysis. Initial crystals of the NS1A-Udorn(85-215):F2F3 complex were obtained by high-throughput robotic screening using service facilities available through the Hauptman Woodward Res. Inst. (Buffalo N.Y.) (Luft et al., 2003; Acton et al., 2005). Crystallization optimization was then carried out for the NS1A-Udorn(85-215):F2F3 complex at Rutgers, yielding diffraction quality bi-pyramid crystal of size 0.15×0.15×0.25 mm 3 . Conditions providing crystals, and a description of these crystals, are presented herein below. Three-wavelength Se-Met multiple anomalous diffraction (MAD) (2.3 A resolution) and a complete native (1.95 Å resolution) data sets were collected at X25 beam line at Brookhaven National Laboratories. The structure was solved by MAD techniques (Hendrickson, 1991) and refined to 1.95 Å resolution, and is currently refined to a R factor of 0.225 and R free of 0.245, respectively.
Crystallization of NS1A Udorn (85-215):F2F3 Complex. Initial crystallization conditions for NS1A Udorn (85-215):F2F3 complex were obtained by using robotic crystallization facility at the Buffalo facility described above. The most promising condition use 1.77 M potassium nitrate (KNO 3 ) at pH 5.0 as precipitant. This initial crystallization condition was optimized manually at Rutgers. Good quality crystals were obtained using 0.25-1.0 M KNO 3 and 10-20% sucrose/glucose as precipitant at pH 5-6. Diffraction quality crystals were obtained when P94S mutant F2F3 was used in the complex, though similar conditions are expected to provide crystals of the complex with the wild-type (P94) F2F3 sequence. The NS1A Udorn (85-215):F2F3 complex was crystallized with the symmetry of the space group P4 1 with cell parameters a=b=50.96, c=205.39 Å and α=β=γ=90°. A variant used in the X-ray crystal structure determination of NS1(85-215):F2F3 complex has Ser in place of Pro at position 94.
FIGS. 4A and 4B disclose the crystal structure of the Udorn NS1A effector domain (residues 85-215) bound to the F2F3 fragment of CPSF30. Consistent with gel filtration data, the complex forms a tetrameric complex, in which two F2F3 molecules bridge two NS1A effector domains. The structure reveals for the first time the novel spatial arrangement of the subunits in the 2 NS1A: 2 F2F3 complex. This tetrameric arrangement was completely unexpected and novel.
Key residues Met106/Met106′ of NS1A are packed in the core of the tetrameric interface or “tetramerization epitope,” explaining its critical role in CPSF30 binding, as discussed above. However, while Met 106/Met106′ are at the core of the tetrameric complex, they are not part of the primary F2F3/CPSF30 binding pocket. FIG. 5 illustrates the F2F3 binding pocket on the surface the Udorn NS1A effector domain. Specific interactions in this primary binding pocket involve residues K110, 1117, 1119, Q121, V180, G183, G184, and W187 of NS1A and residues F97, F98, F103, and K110 of the F3 finger of CPSF30. It should be noted that these residues include not only amino acids in, or adjacent to, the 184-188 sequence previously identified as part of the CPSF30 binding epitope by mutagenesis studies, but also amino acids in other regions in the NS1A protein not previously recognized to be essential for CPSF30 binding. Mutation of residues G183 or G184 in NS1A(85-215) each to Arg or Asp disrupts or reduces F2F2 binding affinity and/or tetramer formation, based on analytical gel filtration measurements without significantly disrupting the native structure of NS1A(85-215) indicated by 15 N- 1 H HSQC NMR spectra (data not shown), demonstrating a functional role of these sites within the CPSF30 binding epitope of NS1A. Recombinant Udorn viruses encoding NS1A proteins in which either G184 or W187 was changed to Arg are attenuated (data not shown), further demonstrating that these amino acids are required for virus replication. The eight residues in the CPSF30-binding epitope of NS1A ( FIG. 5 ) are almost 100% conserved amongst influenza A viruses isolated from humans (Macken et al., 2001), except for Ile117 which is frequently replaced by Met. Based on this structure, disclosed for the first time here, we propose disruption of 2NS1A:2F2F3 tetramerization as a strategy to inhibit influenza A virus in human. Based on our structural data, we further propose that a small molecule inhibitor that binds tightly to the above described conserved epitope and surrounding regions will disrupt CPSF30 binding and will inhibit influenza A virus in humans. This pocket on the surface of the NS1A effector domain is the target of our proposed drug discovery process.
Table 1 describes some of the specific location of the epitopes described herein as the tetramerization, RNA binding and CPSF30 binding epitopes of NS1A.
TABLE 1
Tetramerization, RNA binding and CPSF30 binding epitopes of NS1A.
NS1A
Interacting
amino
amino acids of
acids
F2F3
Remark
F103
L72, Y88,
F103 contributes to both the tetramer interface and the CPSF30-
M93, P111
binding epitope F103 interacts with F2 and F3 domains of CPSF30,
may play a role in defining angle between F2 and F3 appropriately;
mutation of 103 could affect an intermolecular salt bridge between R73
and D125.
L105
P111, F112,
L105 contributes to both the tetramer interface and the CPSF30-
M124 (NS1A-
binding epitope Adjacent to F103 and also interacting at the tetramer
2)
interface with a 2 nd NS1A molecule.
M106
N107
M106 contributes to both the tetramer interface and the CPSF30-
binding epitope. M106I mutation would effect the positioning of N107
(of F2F3) and/or Q121 (NS1A same molecule) involved in F2F3-
NS1A H-bonds.
K110
K110
K110 contributes to the CPSF30-binding epitope. K110 has H-bond
with the main-chain carbonyl of K101 of F2F3.
I117
F102
I117 contributes to the CPSF30-binding epitope. Part of the
hydrophobic pocket that binds F3
I119
F98, F102
I119 contributes to the CPSF30-binding epitope. Part of the
hydrophobic pocket that binds F3
Q121
S105, S106
Q121 contributes to the CPSF30-binding epitope. H-bond with amino
group of S106 and O γ of 105 (both from CPSF30)
D125
R73
D125 contributes to the CPSF30-binding epitope. Salt bridge with
R73 (of CPSF30)
L144
No inter-
L144 is buried into the hydrophobic core of NS1A that probably
molecular
defines the fold of the protein. A mutation of L144 may alter the shape
interaction
of NS1A, resulting in reduced CPSF30 and/or dsRNA binding
activities
V180
Y97, K101,
V180 contributes to the CPSF30-binding epitope. Part of the F3-
F102
binding pocket.
G183
Y97
G183 contributes to the CPSF30-binding epitope. Part of a helix that
forms a wall of the F3-binding pocket. A side-chain may affect
(enhance or disrupt) the binding of F3.
G184
Y97, F98
G184 contributes to the CPSF30-binding epitope. Part of a helix that
forms a wall of the F3-binding pocket. Positioned between Y97 and
F98 side chains. A mutation of G184 would alter the shape of the
pocket and can severely affect the binding of F3.
W187
C96, Y97, F98,
W187 contributes to the CPSF30-binding epitope. Participates in the
F112
pocket formation.
Recently, the crystal structure of the NS lA effector domain (residues 79 to 205) of the influenza A/PR8/34 (PR8) virus strain was reported (Bornholdt and Prasad, 2006). This PR8 influenza strain is adapted for passage in mouse, presumably as a result of mouse adaptation, the PR8 NS gene attenuates virus growth in mammalian cells in tissue culture (Ozaki et al, 2004). The PR8 NS1A protein does not bind F2F3 because it lacks the consensus human sequence at positions 106 (I instead of M) and 103 (S instead of F) (Macken et al, 2001), therefore we can determine if the attenuation of growth in mammalian cells is caused primarily by the changed amino acids at positions 106 and 103 in the PR8 NS1A protein (data not shown). The absence of a CPSF30 binding epitope in the PR8 NS1A protein presumably resulted from the large number of passages in mice that have adapted the virus for replication in mice. Consequently, the 3D structure of effector domain of the PR8 NS1A protein (Bornholdt and Prasad, 2006) is not suitable for structure-based drug discovery efforts. In addition, its structure may differ from that of a NS1A protein containing a functional CPSF30 binding epitope. Indeed, the 3D structures of the Udorn effector domain monomers in our complex are similar to, but not identical with, the structure of the monomers of the PR8 NS1A effector domain structure ( FIG. 6 ). The PR8 NS1A structure does not have a F2F3-binding epitope like that observed in the 3D structure of the Udorn NS1A structure described herein. In particular, the PR8 NS1A structures lack the hydrophobic pocket that binds F2F3 in the NS1A:F2F3 complex. Moreover, the dimeric interface in crystal structure of the PR8 NS1A effector domain has an intermolecular beta-sheet interaction ( FIG. 7 ) that is completely different from the interface in the crystal structure of the Udorn NS1A effector domain bound to F2F3. Therefore, the dimer of the effector domain of the PR8 NS1A protein is not relevant for the binding of CPSF 30 and to our proposed drug-design strategy.
Fluorescence polarization (FP) assay. Fluorescence polarization (FP) is a spectroscopic method that measures the rotational rate of a sample in solution. It applies polarized light to excite a fluorophore and measures the polarization characteristics of the emitted light (Nasir and Jolley, 1999; Roehrl et al., 2004b). If the sample tumbles slowly compared to the lifetime of the fluorescence, the emitted light retains some of the incident polarization. However, if the sample tumbles fast, the emitted light is isotropic. Therefore, the degree of anisotropy (polarization) of the fluorescent light emitted from a sample provides a measure of the fluorophore's rotational correlation time in the bound state. Given appropriate bound-state lifetimes, rotational correlation times, and changes in rotational correlation upon complex formation, FP assays can be used to measure binding affinities and to screen for binding inhibitors (Schade et al., 1996; Seethala and Menzel, 1998; Roehrl et al., 2004a).
FP with fluorescently-labeled F2F3. A FP assay of F2F3 binding by NS1A is being implemented. As mentioned above, complex formation between F2F3 and various effector domain constructs is observed in gel filtration studies (see FIG. 3 ), indicating a dissociation constant K d tighter than low micromolar. These data of FIG. 3 demonstrate the feasibility of implementing a FP assay for detecting NS1A:F2F3 binding. Moreover, excellent HSQC spectra and essentially complete NMR resonance assignments are available for the F2F3 construct (data not shown); these will be used to assess the native structural integrity of fluorescently-labeled CPSF30 fragments.
In one embodiment of the invention, we will generate a fluorescein (or other fluorophore)—labeled F2F3 (Fluo-F2F3) substrate for FP assay. The F2F3 sequence of human CPSF30 contains 7 Lys and 6 Cys residues, and fluorophore labeling requires careful consideration to ensure proper folding with Zn ligation by these six Cys residues. Two primary strategies will be pursued for labeling F2F3: (i) chemical synthesis with a fluorophore label and (ii) synthesis or biosynthesis of an analog suitable for specific labeling. The 61-residue F2F3 is sufficiently short to allow fluorophore labeling by solid phase peptide synthesis (for example, by a commercial supplier, such as New England Peptide, Inc. Gardner, Mass.). The crystal structure of F2F3 bound to the NS1A effector domain indicates that the N-terminal region is not involved in key binding interactions, and suggests that it may be possible to generate shorter constructs with similar binding affinities.
Those constructs that show tight binding can be synthesized in 100 mg amounts and assayed for structural integrity by 15 N- 1 H HSQC NMR analysis at natural isotopic abundance using a 800 MHz NMR system with cryoprobe.
If for some reason this approach is not successful, fluorophone-labeled F2F3 will be produced by overexpression with a ‘flash’ peptide sequence tag (Griffin et al., 1998; Griffin et al., 2000; Abrams, 2002). When the tetra-cysteine tag [NH 2 -Cys-Cys-Pro-Gly-Cys-Cys . . . ] is incorporated into proteins/peptides it can be specifically conjugated to a biarsenyl-fluorophore ligand (sold by Invitrogen as their Lumio-technology). The modification can even specifically label the tetra-cysteine tag in vivo (Griffin et al., 2000), and thus should not react with any of the six cysteine residues on F2F3. If even both of these approaches prove to be problematic for this tandem Zn-finger domain, alternative strategies for fluorophore labeling are available, such as the method of Ting and colleagues (Chen and Ting, 2005) that utilizes biotin ligase together with appropriate cofactors to introduce fluorescein in a short N-terminal acceptor peptide lacking any Cys residues, allowing the fluorophore to be introduced subsequent to forming the Zn fingers.
Using any of the above labeling approaches, or other possible approaches, the labeled F2F3 can then be folded with Zn ligation using the same protocol we have developed for unlabeled F2F3. In exploring each of these approaches, we will verify that the fluorophore in the N-terminal tag becomes sufficiently immobilized in the complex to provide a significant change in fluorescence anisotropy. If required, a more immobilized Cys residue within the F2F3 sequence with be introduced without interfering with Zn-finger formation, using our 3D structure of the NS1A (85-215):F2F3 complex as a guide. Using one of these labeling routes, or any approach for introducing the fluorescence tag, the resulting FP assay will be validated by measuring competition with unlabeled F2F3.
The crystal structure of the complex between NS1A Udorn(85-215) and the F2F3 CPSF30 reveals that most of the intermolecular interactions between NS1A and F2F3 involve the F3 Zn-finger domain ( FIG. 5 ). Accordingly, a smaller flourescein-labeled F3 finger (Fluo-F3), with ˜4 kDa molecular weight, may have preferential properties in developing a FP assay. Though the binding of the NS1A effector domain to Fluo-F3 is likely to be somewhat weaker than the binding to F2F3, the change in rotational correlation time, and thus the signal-to-noise of the FP assay, will be significantly higher using Fluo-F3 than using Fluo-F2F3. These design principles may be advantageous in development of a high throughput FP assay useful in screening for inhibitors of CPSF30 (or variants, mutants, or fragments thereof) binding to NS1A (or variants, mutants, or fragments thereof).
The crystal structure of the complex between NS1A Udorn (85-215) and the F2F3 fragment further suggests that a tandem repeat of the F2F3 fragment, connected by a short flexible linker, F2F3-F2F3, could also bind in a manner similar to the two independent F2F3 molecules, though potentially with much tighter binding affinity. Accordingly, we will generate a variety of F2F3-F2F3 constructs, as outlined below, assay their binding, and assess the oligomerization states of these complexes by gel filtration with light scattering detection. If indeed a tandem repeat F2F3-F2F3 construct can be generated with even tighter binding than F2F3 itself, it will be used in a more sensitive FP assay, capable of detecting only more tightly-binding inhibitors.
The magnitude of the change in fluorescence anisotropy, which determines the signal-to-noise of the FP assay, depends on the change in rotational correlation time of the fluorophore upon complex formation. If required to enhance this change in rotational correlation time, the relative size of the NS1A component of NS1A:CSPF30 (or fragments thereof) complexes described above can be further increased by expression as a larger fusion protein (e.g., fused to maltose binding protein), or by attachment to beads or microscopic particles using, for example, already available constructs of Tables 2, 3, and 4 with either N- or C-terminal hexHis tags, or using other affinity tags.
EXAMPLE 2
Constructs to be Used in Developing Fluorescence Polarization Assay
The crystal structure of the complex between NS1A Udorn (85-215) and the F2F3 fragment was examined to identify potential linking sites so that the C-terminus of one segment of F2F3 (or portion thereof) would have a favorable path for linking to the N-terminus of the second segment. Considerations for favorable linking geometry include the distance between termini to be linked, the path the linker would need to take, and linker composition and length. A common peptide linker composition used for connecting domains in engineered proteins is some combination of Gly and Ser residues, allowing for conformational flexibility and solubility while remaining somewhat neutral in chemical content, e.g. -Gly-Ser-, or -Gly-Ser-Gly, etc.
Constructs were designed based on the crystal structure of the influenza virus NS1A-CTD protein complex with the F2F3 fragment from the human CPSF30 protein, disclosed for this first time in this Disclosure. The expectation is that a single-chain construct of the F2F3 binding regions observed in the crystal structure would bind more tightly to the NS1A dimer than the separate domains, and might have significant antiviral activity.
The structure was examined to identify potential linking sites so that the C-terminus of one segment of F2F3 (or portion thereof) would have a favorable path for linking to the N-terminus of the second segment. Considerations for favorable linking geometry include the distance between termini to be linked, the path the linker would need to take, and linker composition and length. A common peptide linker composition used for connecting domains in engineered proteins is some combination of Gly and Ser residues, allowing for conformational flexibility and solubility while remaining somewhat neutral in chemical content, e.g. -Gly-Ser-, or -Gly-Ser-Gly, etc.
The sequence of CPSF30 F2F3 used for the specific designs is that used in the crystal structure determination, but amino acid replacements can be considered. The N-terminal portion might include a hexa-His or other tag for convenient purification; alternatively a tag might be encoded at the C-terminus of the construct. Other purification tags may be preferable to oligo-His owing to potential interference with the chelation of zinc ions by the F2 and F3 “Zn finger” segments, which is required for the integrity of the three-dimensional structure and for effective binding to NS1A. In all of these F2F3 sequences, residue Pro92 may be substituted by Ser.
The constructs involving single F3 domains (“one finger”) as opposed to F2F3 domains (“two fingers”) are potentially valuable as minimal/miniature versions because the interaction between separate F2F3 chains in the dimer (chains F2F3-A and F2F3-B) is mediated entirely by residues in F3 and does not involve any residues from F2. The F3 domain itself, or variants, could be used as an antiviral drug.
Relatively few of the residues in F2 make important interactions with the NS1A protein in the dimer of dimers; notable exceptions are Leu72 and Arg73, whose side chains interact extensively with NS1A. The Leu72 and Arg73 interactions could be maintained by a strategic linkage of a Leu-Arg or Arg-Leu peptide to Thr91 (proposed N-terminus of the F3 domain construct). L72-T91 distance is 14.2 A; R73-T91 distance is 17.6 A. Possible extensions to the one-finger F3 domain construct would be Leu-Arg-GSGSG-F3 or Arg-Leu-GSGSG-F3 (see proposed constructs 5a and 5b).
F2F3 sequence (numbered as in human CPSF30 protein):
(SEQ ID NO.: 2)
61 71 81 91
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHIDPESK I
Construct 1. F3-F3: Single F3-linker-F3 construct (tandem F3 construct)(abbreviated: (91-116)-linker(11+)-(91-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Thr91 Ca is 33.3 A; linker can be 10+ flexible amino acids;
11: -
(SEQ ID NO.: 3)
GSGSGSGSGSG- also written as -(GS) 5 G-;
13: -
(SEQ ID NO.: 4)
GSGSGSGSGSGSG- also written as -(GS) 6 G-;
(SEQ ID NO.: 5)
91 101 111 linker
116
TKM P ECYFYS KFGECSNKEC PFLHID -(GS) N G -
91 101 111
TKM P ECYFYS KFGECSNKEC PFLHID
C-terminal residue of tandem construct can be D116 or any extension up to 1121; crystal structure extends only to P117 in one copy and E118 in the other. Both N- and C-termini can have extensions including hexaHis and other tags for convenient purification as discussed in the text.
Construct 2. F2F3-F3: Same as previous construct except that the N-terminal portion of the construct encompasses entire F2F3 segment (abbreviated) (60-116)-linker(11+)-(91-116):
(SEQ ID NO.: 6)
61 71 81 91
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHID -
linker 91 101 111 116
(GS) N G - TKM P ECYFYS KFGECSNKEC PFLHID
Construct 3. F2F3-F2F3: F2F3-linker-F2F3 construct (tandem F2F3 construct)(abbreviated: (60-116)-linker(15+)-(62-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Gly62 Ca is 51.1 Å; linker should be 14+ flexible amino acids:
15: -
(SEQ ID NO.: 7)
GSGSGSGSGSGSGSG- also written as -(GS) 7 G-;
17: -
(SEQ ID NO.: 8)
GSGSGSGSGSGSGSGSG- also written as -(GS) 8 G-;
(SEQ ID NO.: 9)
61 71 81 91 101
M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
111
KFGECSNKEC PFLHID -
linker 62 71 81
(GS) N G - GEKTVVCKH WLRGLCKKGD QCEFLHEYDM
91 101 111
TKM P ECYFYS KFGECSNKEC PFLHID.
Construct 4. F3 -F2F3: F3 -linker-F2F3 construct (abbreviated: (91-116)-linker(15+)-(62-116)). Distance from F2F3-A Asp116 Ca to F2F3-B Gly62 Ca is 51.1 Å; linker should be 14+ flexible amino acids.
(SEQ ID NO.: 10)
91 101 111 116 linker
TKM P ECYFYS KFGECSNKEC PFLHID - (GS) N G -
62 71 81 91
GEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKM P ECYFYS
101 111
KFGECSNKEC PFLHID
Construct 5. XF3-F3: Extended F3-linker-F3 construct. Linker 1 will link a Leu-Arg or Arg-Leu dipeptide to the one-finger F3 domain in a mode to incorporate the important L72 and R73 side-chain interactions from F2 that are otherwise missing. Linker 2 can be 10+ flexible amino acids:
Construct 5a (abbreviated: Leu-Arg-linker(5+)-(91-116)-linker(11+)-(91-116)):
(SEQ ID NO.: 11)
72 73 linker 1 91 101
Leu-Arg - GSGSG - TKM P ECYFYS KFGECSNKEC
111 116 linker 2
PFLHID - (GS) N G -
91 101 111 116
TKM P ECYFYS KFGECSNKEC PFLHID
Construct 5b (abbreviated: Arg-Leu-linker(5+)-(91-116)-linker(11+)-(91-116)):
(SEQ ID NO.: 12)
73 72 linker 1 91 101
Arg-Leu - GSGSG - TKM P ECYFYS KFGECSNKEC
111 116 linker 2
PFLHID - (GS) N G -
91 101 111 116
TKM P ECYFYS KFGECSNKEC PFLHID
Each of the constructs 1-5b above, and variants thereof, will inhibit CPSF30 binding by NS1A, and can potentially be used as lead compounds for drug development and/or as antiviral drugs useful in preventing or treating influenza A infection in humans, poultry (e.g. chicken), and other animals.
Structure-based Lead Optimization using X-ray Crystallography and NMR. The sample preparation and structural characterization of NS1A effector domains from multiple influenza strains, allow the use of both NMR and X-ray crystallography in hit validation, lead compound optimization, and drug discovery.
Crystallography for lead optimization. X-ray analysis has historically been very important to structure-based inhibitor design. Compounds identified as inhibitor “hits” by kinetic assays can be used to form complexes with the target protein. X-ray analysis will reveal the mode of inhibitor binding and act as a basis for further inhibitor design. Crystal inhibitor complexes can also be formed by soaking inhibitors into preformed crystals, or complexes may be grown by co-crystallization. The latter case may be necessary if the complex triggers conformational changes. In either case, diffraction data is collected on a rotating anode source, processed, and converted to electron density maps. The orientation and occupancy of the inhibitors will be observed and compared with binding modes predicted from virtua 1 screening or models from earlier design cycles. In this way, inhibitors analyzed in one cycle of design will feed into subsequent rounds of structural analysis and re-design in the general process of structure-based drug design (Kuhn 2002; Scapin 2006)
Cocrystallization and Crystal soaks. Using crystallization conditions that we have already optimized for the NS1A effector domains, described above, cocrystallizations and crystal soaks can be carried out with lead compounds identified in our high throughput screening efforts. Trials will be carried out to crystallize NS1A effector domain:lead compound complexes. Diffraction data can be collected using either home or synchrotron X-ray sources and the resulting difference electron density maps and 3D structures can be used to characterize small molecule binding epitopes and bound-state conformations. These data can be used screening for lead compounds either one at a time or in high throughput format, lead compound validation, and optimization of lead compounds, using methods familiar to a person skilled in the art.
NMR for lead identification optimization. NMR is also a powerful method for validating intermolecular interactions, and is used extensively in commercial pharmaceutical drug discovery efforts to identify lead compounds and their protein binding sites (Shuker et al., 1996; Hajduk et al., 1997; Moore, 1999a, 1999b; Muegge et al., 1999; Moy et al., 2001; Powers, 2002; Lepre et al., 2004; Rush and Powers, 2004; Mercier et al., 2006; Petros et al., 2006). NMR chemical shift perturbations, of either the protein or the ligand, can be used for screening for small molecule lead compounds, validating initial small molecule hits identified with htp or virtual screening assays, locating the corresponding binding site in the 3D protein structure, and to guide rational lead optimization. NMR methods uniquely complement crystallography studies. Strengths of NMR analysis methods include (i) the ability to detect even weak (k d up to ˜500 micromolar) binding interactions, (ii) compatibility with systems that undergo structural changes upon ligand binding which may not be accommodated by a crystalline lattice, (iii) the ability to adjust solvent conditions over a wide range, and (iv) high sensitivity and very low sample requirements.
Using NS1A effector domain constructs that have already been shown to provide high quality HSQC spectra (e.g., FIG. 2 ), NMR chemical shift perturbation can be used to validate initial small molecule hits identified with high-throughput (htp) or virtual screening assays, locating the corresponding binding site in the 3D protein structure, and for rational lead optimization. Hits identified in htp FP assays will be characterized by assessing perturbations in HSQC spectra for which resonance assignments will be available, and interpreting these effects on the available 3D structures of NS1 effector domains. Some methods suitable for lead compound screening, identification, and optimization envisioned for use with our invention are summarized in C. A. Lepre, J. M, Moore, and J. W. Peng, Theory and Applications of NMR-based Screening in Pharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)), which is incorporated herein by reference. The NMR infrastructure required for such work are available at most large research institutions, including by not limited to Rutgers University, and include 5 mm 600 and 800 MHz NMR cryoprobe systems, as well as a 1 mm 600 MHz NMR equipped with an automated sample changer. The cryoprobes enable recording of high-quality HSQC data using 150 microliter samples at protein concentrations as low as 10 micromolar, and the 1 mm NMR probe provides high quality HSQC data on 7 microliter samples at 100 micromolar concentrations. Such NMR technologies allow NMR screening for lead compound optimization with as little as ˜500 nanomoles of each sample. Where appropriate, the 3D structures of tightly bound small molecule lead compounds may also be determined by NMR methods if they cannot be solved by crystallographic methods. These data will be used in redesign and lead optimization as outlined for crystallographic data above.
Expressed soluble constructs of NS1A outlined in Tables 2, 3 and 4, or their variants, can also be used to screen for small molecule lead compounds using NMR detection of resonances of the small molecule, using limits desribed by (but not limited to) C. A. Lepre, J. M. Moore, and J. W. Peng, Theory and Applications of NMR-based Screening in Pharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)).
Where appropriate, the 3D structures of tightly bound small molecule lead compounds may also be determined by NMR methods if they cannot be solved by crystallographic methods. These data will be used in redesign and lead optimization using synthetic chemistry, as outlined for crystallographic data above.
Antiviral assays. Having identified inhibitors of the interaction between NS1A and CPSF30, the inhibitors would be tested for their ability to inhibit influenza A virus replication in tissue culture studies. Plaque reduction assays in MDCK cells will be used to assay compounds for their ability to inhibit influenza A virus replication (Twu et al., 2006). Monolayers of MDCK cells will be infected with approximately 100 plaque-forming units (PFU) of influenza A/Udorn/72 virus, and after virus adsorption the cells will be overlaid with agar containing a concentration of a compound ranging from 0.001 micrograms/ml to 10 micrograms/ml. Plaques will be counted in duplicate plates and compared to the number of plaques in controls not exposed to the chemical. In parallel cytotoxicity evaluations of lead compounds would be carried out on MDCK cells using the Roche reagent WST-1 (Berridge et al., 2005). The rate of WST-1 cleavage by mitochondrial dehydrogenases, yielding a product with absorbance at 450 nm, correlates with the number of viable cells. These assays will be carried out in 96-well tissue culture plates, and cell viability will be assayed by determining absorbance at 450nm using an ELISA plate reader. Once the most promising lead compounds with low cytotoxicity in both MDCK and human (A549) cells have been identified, we will determine the effect of several concentrations of the compounds on the rate and extent of virus replication during multiple-cycle growth in MDCK cells. The compounds with the greatest inhibitory activity at the lowest concentrations will be used for subsequent studies in a suitable animal model (ferrets).
Applications of NS1A:CPSF30 Inhibitors. These inhibitors can be developed into antiviral drugs that will be effective in the control of influenza virus epidemics and pandemics in humans. Because there is the potential for such epidemics to be man-made, i.e., using influenza A virus as a bioterrorist weapon, such antivirals would also be crucial in this situation. Influenza antiviral drugs will also be important for the control of influenza A infections in commercial poultry stocks, such as chickens.
TABLE 2
pET-based vectors for NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
Full-length
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
1-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
73-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
85-215
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
91-215
C-His
Not attempted
C-His
C-His
1-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
85-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
73-211
N-His and C-His
N-His and C-His
N-His and C-His
N-His and C-His
91-211
C-His
Not attempted
Not attempted
Not attempted
85-204
C-His
C-His
C-His
C-His
91-204
C-His
Not attempted
C-His
C-His
TABLE 3
N-terminal His tag NS1 Expression/Solubility results for
NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
FL
yes/low
yes/low
no/na
yes/low
1-215
yes/low
yes/low
yes/no
yes/low
73-215
yes/no
yes/med
yes/no
yes/low
85-215
yes/low
yes/low
yes/low
yes/med
1-211
yes/no
yes/low
yes/no
yes/low
85-211
yes/low
yes/no
yes/med
yes/med
73-211
yes/low
yes/no
yes/med
yes/low
TABLE 4
C-terminal His tag NS1 Expression/Solubility results for
NS1A proteins and fragments from various flu strains.
1918
HK97
VN04
Udorn
FL
yes/low
yes/no
no/na
yes/low
1-215
yes/no
yes/medium
yes/no
yes/no
73-215
na
na
yes/no
yes/low
85-215
yes/medium
yes/good
yes/low
yes/low
91-215
yes/low
yes/low
na
yes/low
1-211
no/na
na
yes/no
na
85-211
yes/no
yes/no
yes/low
yes/no
73-211
na
yes/no
yes/good
yes/no
91-211
yes/no
na
na
na
85-204
yes/low
yes/low
yes/low
yes/low
91-204
yes/no
yes/no
na
yes/no
Creating Attenuated Influenza Virus Strains Suitable for Avian and Human Influenza Vaccine Development. The structural information disclosed here can be combined with site-directed mutagenesis data for NS1A to engineer attenuated influenza A virus strains suitable for use as live attenuated vaccines in humans and livestock. Multiple, weakly attenuating mutations will be created in the CPSF30 and dsRNA-binding epitopes to generate NS1 proteins with reduced binding affinity in vitro. The effects of these mutations on the structural integrity of NS1A variants can be assessed with HSQC NMR data and/or crystallization and X-ray crystallography. These data will then be used to engineer viral strains of influenza A with various degrees of attenuation. These viral strains will be engineered to contain multiple base changes to minimize the potential of the virus to revert to virulence. Such influenza A viruses would be attenuated in normal cells, and in humans and animals, but would not be attenuated in cells lacking interferon genes (e.g. cell culture Vero cells), thereby enabling the production of large amounts of these attenuated viruses suitable for use as a live virus vaccine.
Methods for development of attenuated flu vaccines are described in U.S. Provisional Patent Application Ser. No. 60/737,742, “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,”, and PTC Patent Application Filed Nov. 17, 2006 “Novel Compositions and Vaccines Against Influenza and Influenza B Infections,” relevant portions and tables incorporated herein by reference, relevant portions incorporated herein by reference.
A person of ordinary skill in the art will understand that because of the degeneracy of the genetic code, a large number of nucleic acid sequences can be generated in accordance with this invention. The production of the viruses of the instant invention (or the respective recombinant NS1A protein or respective NS1B protein comprising said amino acid sequences) can be achieved by recombinant DNA technology. Nucleic acid sequences encoding the amino acid sequences of the instant invention can be produced using methods well known in the art, including, for example, chemical synthesis, PCR and site-directed mutagenesis.
The instant invention provides recombinant influenza A virus comprising the amino acid sequences which are at least 70% identical but less than 100% identical either to dsRNA binding domains of NS1A. These viruses may be generated, for example, by reverse genetic system, whereby influenza virus can be generated by transfection of multiple DNAs without a helper virus. This technique was described in Fodor et al., 1999. Essentially, in that study the technique involved transfecting into a host cell a combination of plasmids containing cDNAs for the viral RNA segments (including NS1 proteins), proteins of viral RNA dependent polymerase complex (PB1, PB2, and PA), and nucleoprotein. Further, it is possible to transfect host cells (such as, for example 293 cells or Vero cells) with a plasmid encoding a recombinant NS1A protein (for rescuing influenza A viral phenotype) containing the appropriate amino acid sequence of the instant invention. The resulting viruses may be used for creation of vaccines, as described below.
In another embodiment, the virus can be propagated in suitable host, such as, for example, chicken eggs, without a need for transforming a host cell with multiple plasmids. In this embodiment, essentially, clinical isolates of human influenza virus are taken from infected patients and are reassorted in embryonated chicken eggs with laboratory-adapted master strains of high-growth donor viruses.
To prepare the recombinant NS1A viruses for different purposes (including, without limitations, the use of the virus as a vaccine or a part thereof), each of these mutations may be carried out individually on constructs of NS1A suitable for biochemical characterization, possibly including but not limited to the constructs outlined in Tables 3 and 4. Other variants of NS1A or affinity tags (e.g. FLAG tags) may also be used. These proteins may be purified and characterized with respect to structural integrity by comparing the circular dichroism and/or NMR spectrum and/or X-ray crystal structures with those of the corresponding wild-type NS1 construct. The several constructs may then be assayed for dsRNA binding as described elsewhere (Chien et al., 2004), or using other methods of assessing protein-dsRNA binding affinities commonly used for such studies, such as, for example, sedimentation equilibrium, gel electrophoresis, or gel filtration chromatography. These data will be used to assess the effect of single site mutants at these sites revealed by the structural models to be important for dsRNA recognition. Further, sets of double, triple, and quadruple mutants of residues in the CPSF30 binding epitope, tetramer interface, dsRNA binding epitope, and combinations thereof would also be generated in these NS1A constructs and assessed for structural integrity and binding activities in vitro. This experimental design will allow a person of the ordinary skill in the art to identify mutant forms of NS1A and NS1A varients with minimal structural disruption but with reduced CPSF30 and/or dsRNA binding affinity.
The invention encompasses methods of selecting viruses which have the desired phenotype, i.e., viruses which have low or no dsRNA binding activity, whether obtained from natural variants, spontaneous variants (i.e., variants which evolve during virus propagation), mutagenized natural variants, reassortants and/or genetically engineered viruses. Such viruses can be best screened in differential growth assays that compare growth in host systems which have attenuated and normal immune response to influenza A viruses. Viruses which demonstrate better growth in the hosts having the attenuated response versus the normal response are selected; preferably, viruses which grow to titers at least one log greater in the host systems with the attenuated response as compared to the host system with the normal response are selected.
The present invention also encompasses methods of growing and isolating mutated viruses having altered dsRNA binding activity in cells and cell lines which naturally exhibit an attenuated response to viral infections as compared to wild-type cells. In a particular preferred embodiment, the present invention relates to methods of growing the viruses of the instant invention in Vero cells.
It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.
It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.
All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
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Puthavathana, P., Auewarakul, P., Charoenying, P. C., Sangsiriwut, K., Pooruk, P., Boonnak, K., Khanyok, R., Thawachsupa, P., Kijphati, R., and Sawanpanyalert, P. 2005. Molecular characterization of the complete genome of human influenza H5N1 virus isolates from Thailand. J. Gen. Virol. 86: 423-33.
Reid, A. H., Taubenberger, J. K., and Fanning, T. G. 2001. The 1918 Spanish influenza: integrating history and biology. Microbiol. Infect. 3: 81-7.
Reid, A. H., Taubenberger, J. K., and Fanning, T. G. 2004. Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus. Nat Rev Microbiol 2: 909-14.
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Roehrl, M. H. A., Wang, J. Y., and Wagner, G. 2004b. A general framework for development and data analysis of competitive high-throughput screens for small-molecule inhibitors of protein-protein interactions by fluorescence polarization. Biochemistry 43: 16056-66.
Rush, T. S., 3rd, and Powers, R. 2004. The application of x-ray, NMR, and molecular modeling in the design of MMP inhibitors. Curr Top Med Chem 4: 1311-27.
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HEADER
−−−−
XX−XXX−XX xxxx
COMPND
−−−
REMARK
3
REMARK
3
REFINEMENT.
REMARK
3
PROGRAM:
REFMAC 5.2.0005
REMARK
3
AUTHORS:
MURSHUDOV, VAGIN, DODSON
REMARK
3
REMARK
3
REFINEMENT TARGET:
MAXIMUM LIKELIHOOD
REMARK
3
REMARK
3
DATA USED IN REFINEMENT.
REMARK
3
RESOLUTION RANGE HIGH (ANGSTROMS):
1.95
REMARK
3
RESOLUTION RANGE LOW (ANGSTROMS):
25.00
REMARK
3
DATA CUTOFF (SIGMA(F)):
NONE
REMARK
3
COMPLETENESS FOR RANGE (%):
97.88
REMARK
3
NUMBER OF REFLECTIONS:
35935
REMARK
3
REMARK
3
FIT TO DATA USED IN REFINEMENT.
REMARK
3
CROSS−VALIDATION METHOD:
THROUGHOUT
REMARK
3
FREE R VALUE TEST SET SELECTION:
RANDOM
REMARK
3
R VALUE (WORKING + TEST SET):
0.19912
REMARK
3
R VALUE (WORKING SET):
0.19794
REMARK
3
FREE R VALUE:
0.23607
REMARK
3
FREE R VALUE TEST SET SIZE (%):
3.1
REMARK
3
FREE R VALUE TEST SET COUNT:
1159
REMARK
3
REMARK
3
FIT IN THE HIGHEST RESOLUTION BIN.
REMARK
3
TOTAL NUMBER OF BINS USED:
20
REMARK
3
BIN RESOLUTION RANGE HIGH:
1.950
REMARK
3
BIN RESOLUTION RANGE LOW:
2.000
REMARK
3
REFLECTION IN BIN (WORKING SET):
2372
REMARK
3
BIN COMPLETENESS (WORKING(%):
87.48
REMARK
3
BIN R VALUE (WORKING SET):
0.251
REMARK
3
BIN FREE R VALUE SET COUNT:
66
REMARK
3
BIN FREE R VALUE:
0.310
REMARK
3
REMARK
3
NUMBER OF NON−HYDROGEN ATOMS USED IN REFINEMENT.
REMARK
3
ALL ATOMS:
3121
REMARK
3
REMARK
3
B VALUES.
REMARK
3
FROM WILSON PLOT (A**2):
NULL
REMARK
3
MEAN B VALUE (OVERALL, A**2):
36.438
REMARK
3
OVERALL ANISOTROPIC B VALUE.
REMARK
3
B11 (A**2):
1.36
REMARK
3
B22 (A**2):
1.36
REMARK
3
B33 (A**2):
−2.71
REMARK
3
B12 (A**2):
0.00
REMARK
3
B13 (A**2):
0.00
REMARK
3
B23 (A**2):
0.00
REMARK
3
REMARK
3
ESTIMATED OVERALL COORDINATE ERROR.
REMARK
3
ESU BASED ON R VALUE (A):
0.143
REMARK
3
ESU BASED ON FREE R VALUE (A):
0.138
REMARK
3
ESU BASED ON MAXIMUM LIKELIHOOD (A):
0.102
REMARK
3
ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2):
3.568
REMARK
3
REMARK
3
CORRELATION COEFFICIENTS.
REMARK
3
CORRELATION COEFFICIENT FO−FC:
0.956
REMARK
3
CORRELATION COEFFICIENT FO−FC FREE:
0.942
REMARK
3
REMARK
3
RMS DEVIATIONS FROM IDEAL VALUES
COUNT
RMS
WEIGHT
REMARK
3
BOND LENGTHS REFINED ATOMS (A):
2997
;
0.020
;
0.022
REMARK
3
BOND ANGLES REFINED ATOMS
4042
;
1.715
;
1.956
(DEGREES):
REMARK
3
TORSION ANGLES, PERIOD 1 (DEGREES):
357
;
6.180
;
5.000
REMARK
3
TORSION ANGLES, PERIOD 2 (DEGREES):
137
;
34.186
;
24.015
REMARK
3
TORSION ANGLES, PERIOD 3 (DEGREES):
548
;
14.846
;
15.000
REMARK
3
TORSION ANGLES, PERIOD 4 (DEGREES):
16
;
17.200
;
15.000
REMARK
3
CHIRAL- CENTER RESTRAINTS (A**3):
435
;
0.126
;
0.200
REMARK
3
GENERAL PLANES REFINED ATOMS (A):
2240
;
0.007
;
0.020
REMARK
3
NON-BONDED CONTACTS REFINED
1262
;
0.212
;
0.200
ATOMS (A):
REMARK
3
NON- BONDED TORSION REFINED
2012
;
0.311
;
0.200
ATOMS (A):
REMARK
3
H- BOND (X...Y) REFINED ATOMS (A):
162
;
0.165
;
0.200
REMARK
3
POTENTIAL METAL−ION REFINED
1
;
0.109
;
0.200
ATOMS (A):
REMARK
3
SYMMETRY VDW REFINED ATOMS (A):
85
;
0.232
;
0.200
REMARK
3
SYMMETRY H−BOND REFINED
14
;
0.182
;
0.200
ATOMS (A):
REMARK
3
REMARK
3
ISOTROPIC THERMAL FACTOR
COUNT
RMS
WEIGHT
RESTRAINTS.
REMARK
3
MAIN- CHAIN BOND REFINED ATOMS
1889
;
1.376
;
1.500
(A**2):
REMARK
3
MAIN- CHAIN ANGLE REFINED ATOMS
2920
;
2.197
;
2.000
(A**2):
REMARK
3
SIDE- CHAIN BOND REFINED ATOMS
1300
;
2.913
;
3.000
(A**2):
REMARK
3
SIDE- CHAIN ANGLE REFINED ATOMS
1122
;
4.495
;
4.500
(A**2):
REMARK
3
REMARK
3
NCS RESTRAINTS STATISTICS
REMARK
3
NUMBER OF NCS GROUPS:
NULL
REMARK
3
REMARK
3
REMARK
3
TLS DETAILS
REMARK
3
NUMBER OF TLS GROUPS:
NULL
REMARK
3
REMARK
3
REMARK
3
BULK SOLVENT MODELLING.
REMARK
3
METHOD USED:
MASK
REMARK
3
PARAMETERS FOR MASK CALCULATION
REMARK
3
VDW PROBE RADIUS:
1.20
REMARK
3
ION PROBE RADIUS:
0.80
REMARK
3
SHRINKAGE RADIUS:
0.80
REMARK
3
REMARK
3
OTHER REFINEMENT REMARKS:
REMARK
3
HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
REMARK
3
CRYST1
50.961
50.961
205.387
90.00
90.00
90.00
P 41
SCALE1
0.019623
0.000000
0.000000
0.00000
SCALE2
0.000000
0.019623
0.000000
0.00000
SCALE3
0.000000
0.000000
0.004869
0.00000
ATOM
1
N
PRO
A
85
−26.122
32.840
39.164
1.00
67.70
N
ATOM
2
CA
PRO
A
85
−26.884
33.641
38.196
1.00
67.41
C
ATOM
3
CB
PRO
A
85
−26.347
35.071
38.415
1.00
67.69
C
ATOM
4
CG
PRO
A
85
−25.675
35.066
39.826
1.00
68.21
C
ATOM
5
CD
PRO
A
85
−25.736
33.625
40.355
1.00
68.25
C
ATOM
6
C
PRO
A
85
−26.665
33.197
36.735
1.00
66.66
C
ATOM
7
O
PRO
A
85
−25.599
32.636
36.413
1.00
67.05
O
ATOM
8
N
ALA
A
86
−27.666
33.441
35.876
1.00
65.01
N
ATOM
9
CA
ALA
A
86
−27.562
33.211
34.427
1.00
63.22
C
ATOM
10
CB
ALA
A
86
−28.909
33.479
33.746
1.00
63.77
C
ATOM
11
C
ALA
A
86
−26.438
34.049
33.773
1.00
61.60
C
ATOM
12
O
ALA
A
86
−26.536
35.280
33.715
1.00
61.58
O
ATOM
13
N
SER
A
87
−25.385
33.361
33.294
1.00
59.11
N
ATOM
14
CA
SER
A
87
−24.164
33.987
32.734
1.00
56.32
C
ATOM
15
CB
SER
A
87
−23.014
32.968
32.609
1.00
56.60
C
ATOM
16
OG
SER
A
87
−22.933
32.092
33.722
1.00
55.71
O
ATOM
17
C
SER
A
87
−24.439
34.600
31.365
1.00
54.09
C
ATOM
18
O
SER
A
87
−25.441
34.273
30.727
1.00
53.42
O
ATOM
19
N
ARG
A
88
−23.560
35.507
30.928
1.00
51.11
N
ATOM
20
CA
ARG
A
88
−23.691
36.103
29.599
1.00
49.05
C
ATOM
21
CB
ARG
A
88
−22.704
37.255
29.435
1.00
49.01
C
ATOM
22
CG
ARG
A
88
−23.079
38.587
30.081
1.00
52.03
C
ATOM
23
CD
ARG
A
88
−21.921
39.576
29.841
1.00
51.77
C
ATOM
24
NE
ARG
A
88
−21.495
39.538
28.437
1.00
56.44
N
ATOM
25
CZ
ARG
A
88
−20.325
39.972
27.964
1.00
56.82
C
ATOM
26
NH1
ARG
A
88
−19.396
40.504
28.770
1.00
52.97
N
ATOM
27
NH2
ARG
A
88
−20.093
39.853
26.662
1.00
58.69
N
ATOM
28
C
ARG
A
88
−23.391
35.056
28.527
1.00
45.17
C
ATOM
29
O
ARG
A
88
−22.545
34.198
28.745
1.00
43.46
O
ATOM
30
N
TYR
A
89
−24.092
35.139
27.399
1.00
42.80
N
ATOM
31
CA
TYR
A
89
−23.763
34.336
26.204
1.00
42.12
C
ATOM
32
CB
TYR
A
89
−24.984
33.639
25.610
1.00
43.89
C
ATOM
33
CG
TYR
A
89
−25.584
32.586
26.481
1.00
49.25
C
ATOM
34
CD1
TYR
A
89
−26.692
32.877
27.301
1.00
53.80
C
ATOM
35
CE1
TYR
A
89
−27.278
31.876
28.129
1.00
55.07
C
ATOM
36
CZ
TYR
A
89
−26.745
30.583
28.120
1.00
53.29
C
ATOM
37
OH
TYR
A
89
−27.307
29.603
28.924
1.00
52.63
O
ATOM
38
CE2
TYR
A
89
−25.633
30.272
27.320
1.00
52.65
C
ATOM
39
CD2
TYR
A
89
−25.059
31.275
26.501
1.00
51.55
C
ATOM
40
C
TYR
A
89
−23.103
35.144
25.095
1.00
39.05
C
ATOM
41
O
TYR
A
89
−23.578
36.222
24.734
1.00
39.30
O
ATOM
42
N
ILE
A
90
−22.007
34.604
24.565
1.00
35.95
N
ATOM
43
CA
ILE
A
90
−21.374
35.101
23.343
1.00
33.00
C
ATOM
44
CB
ILE
A
90
−19.815
35.017
23.400
1.00
33.20
C
ATOM
45
CG1
ILE
A
90
−19.213
35.693
24.659
1.00
31.66
C
ATOM
46
CD1
ILE
A
90
−19.623
37.181
24.946
1.00
34.93
C
ATOM
47
CG2
ILE
A
90
−19.218
35.494
22.065
1.00
32.68
C
ATOM
48
C
ILE
A
90
−21.815
34.214
22.179
1.00
31.70
C
ATOM
49
O
ILE
A
90
−21.772
32.988
22.277
1.00
30.65
O
ATOM
50
N
THR
A
91
−22.206
34.848
21.084
1.00
30.72
N
ATOM
51
CA
THR
A
91
−22.721
34.177
19.892
1.00
30.64
C
ATOM
52
CB
THR
A
91
−24.272
34.313
19.747
1.00
30.93
C
ATOM
53
OG1
THR
A
91
−24.641
35.693
19.595
1.00
31.58
O
ATOM
54
CG2
THR
A
91
−25.010
33.726
20.961
1.00
31.12
C
ATOM
55
C
THR
A
91
−21.973
34.698
18.654
1.00
30.39
C
ATOM
56
O
THR
A
91
−22.425
35.616
18.014
1.00
29.92
O
ATOM
57
N
ASP
A
92
−20.789
34.150
18.367
1.00
29.53
N
ATOM
58
CA
ASP
A
92
−20.088
34.437
17.103
1.00
29.38
C
ATOM
59
CB
ASP
A
92
−18.705
33.737
16.987
1.00
29.06
C
ATOM
60
CG
ASP
A
92
−17.630
34.283
17.934
1.00
30.61
C
ATOM
61
OD1
ASP
A
92
−17.802
35.375
18.537
1.00
29.26
O
ATOM
62
OD2
ASP
A
92
−16.577
33.585
18.121
1.00
25.92
O
ATOM
63
C
ASP
A
92
−20.917
33.920
15.919
1.00
29.87
C
ATOM
64
O
ASP
A
92
−20.852
34.518
14.848
1.00
30.63
O
ATOM
65
N
MET
A
93
−21.646
32.798
16.090
1.00
28.80
N
ATOM
66
CA
MET
A
93
−22.334
32.178
14.985
1.00
28.53
C
ATOM
67
CB
MET
A
93
−22.254
30.625
15.045
1.00
28.56
C
ATOM
68
CG
MET
A
93
−20.873
30.056
14.617
1.00
23.17
C
ATOM
69
SD
MET
A
93
−20.816
28.244
14.793
1.00
22.81
S
ATOM
70
CE
MET
A
93
−20.351
28.121
16.505
1.00
21.77
C
ATOM
71
C
MET
A
93
−23.785
32.591
14.932
1.00
31.52
C
ATOM
72
O
MET
A
93
−24.416
32.810
15.973
1.00
32.72
O
ATOM
73
N
THR
A
94
−24.311
32.686
13.709
1.00
33.84
N
ATOM
74
CA
THR
A
94
−25.754
32.818
13.520
1.00
35.14
C
ATOM
75
CB
THR
A
94
−26.080
33.245
12.094
1.00
35.65
C
ATOM
76
OG1
THR
A
94
−25.554
32.285
11.173
1.00
35.99
O
ATOM
77
CG2
THR
A
94
−25.481
34.615
11.807
1.00
36.80
C
ATOM
78
C
THR
A
94
−26.448
31.512
13.841
1.00
35.97
C
ATOM
79
O
THR
A
94
−25.818
30.446
13.913
1.00
34.20
O
ATOM
80
N
ILE
A
95
−27.761
31.587
14.029
1.00
36.97
N
ATOM
81
CA
ILE
A
95
−28.575
30.410
14.266
1.00
38.79
C
ATOM
82
CB
ILE
A
95
−30.070
30.801
14.496
1.00
38.82
C
ATOM
83
CG1
ILE
A
95
−30.205
31.659
15.779
1.00
41.36
C
ATOM
84
CD1
ILE
A
95
−31.709
31.841
16.326
1.00
42.00
C
ATOM
85
CG2
ILE
A
95
−30.911
29.558
14.598
1.00
41.63
C
ATOM
86
C
ILE
A
95
−28.396
29.378
13.116
1.00
37.69
C
ATOM
87
O
ILE
A
95
−28.268
28.199
13.365
1.00
38.70
O
ATOM
88
N
GLU
A
96
−28.378
29.842
11.878
1.00
36.92
N
ATOM
89
CA
GLU
A
96
−28.104
28.999
10.700
1.00
36.29
C
ATOM
90
CB
GLU
A
96
−28.239
29.823
9.409
1.00
36.39
C
ATOM
91
CG
GLU
A
96
−28.227
29.016
8.087
1.00
38.37
C
ATOM
92
CD
GLU
A
96
−26.817
28.589
7.614
1.00
40.56
C
ATOM
93
OE1
GLU
A
96
−25.874
29.406
7.689
1.00
39.66
O
ATOM
94
OE2
GLU
A
96
−26.666
27.421
7.174
1.00
40.00
O
ATOM
95
C
GLU
A
96
−26.709
28.344
10.788
1.00
35.41
C
ATOM
96
O
GLU
A
96
−26.605
27.137
10.614
1.00
33.83
O
ATOM
97
N
GLU
A
97
−25.657
29.114
11.117
1.00
34.89
N
ATOM
98
CA
GLU
A
97
−24.290
28.538
11.192
1.00
34.19
C
ATOM
99
CB
GLU
A
97
−23.215
29.612
11.389
1.00
34.50
C
ATOM
100
CG
GLU
A
97
−22.913
30.437
10.153
1.00
34.90
C
ATOM
101
CD
GLU
A
97
−22.021
31.629
10.505
1.00
38.47
C
ATOM
102
OE1
GLU
A
97
−22.183
32.188
11.630
1.00
34.46
O
ATOM
103
OE2
GLU
A
97
−21.153
31.993
9.675
1.00
39.78
O
ATOM
104
C
GLU
A
97
−24.222
27.492
12.285
1.00
34.41
C
ATOM
105
O
GLU
A
97
−23.610
26.431
12.128
1.00
33.26
O
ATOM
106
N
LEU
A
98
−24.931
27.757
13.379
1.00
33.38
N
ATOM
107
CA
LEU
A
98
−24.975
26.854
14.496
1.00
33.56
C
ATOM
108
CB
LEU
A
98
−25.625
27.616
15.676
1.00
35.16
C
ATOM
109
CG
LEU
A
98
−25.697
27.103
17.089
1.00
36.28
C
ATOM
110
CD1
LEU
A
98
−24.280
27.030
17.629
1.00
37.99
C
ATOM
111
CD2
LEU
A
98
−26.556
28.164
17.855
1.00
36.53
C
ATOM
112
C
LEU
A
98
−25.721
25.558
14.186
1.00
33.48
C
ATOM
113
O
LEU
A
98
−25.383
24.495
14.740
1.00
31.52
O
ATOM
114
N
SER
A
99
−26.735
25.649
13.311
1.00
32.52
N
ATOM
115
CA
SER
A
99
−27.648
24.548
13.055
1.00
34.15
C
ATOM
116
CB
SER
A
99
−29.071
25.062
12.750
1.00
33.43
C
ATOM
117
OG
SER
A
99
−29.498
25.903
13.802
1.00
40.37
O
ATOM
118
C
SER
A
99
−27.246
23.698
11.864
1.00
32.87
C
ATOM
119
O
SER
A
99
−27.754
22.584
11.728
1.00
32.22
O
ATOM
120
N
ARG
A
100
−26.348
24.228
11.031
1.00
31.55
N
ATOM
121
CA
ARG
A
100
−25.947
23.591
9.759
1.00
31.41
C
ATOM
122
CB
ARG
A
100
−24.975
24.509
9.028
1.00
30.90
C
ATOM
123
CG
ARG
A
100
−24.884
24.295
7.526
1.00
30.96
C
ATOM
124
CD
ARG
A
100
−23.727
25.099
6.940
1.00
30.21
C
ATOM
125
NE
ARG
A
100
−23.929
26.551
7.061
1.00
31.23
N
ATOM
126
CZ
ARG
A
100
−22.966
27.437
6.886
1.00
33.84
C
ATOM
127
NH1
ARG
A
100
−21.733
27.018
6.593
1.00
32.14
N
ATOM
128
NH2
ARG
A
100
−23.220
28.737
7.013
1.00
33.44
N
ATOM
129
C
ARG
A
100
−25.234
22.286
10.023
1.00
30.72
C
ATOM
130
O
ARG
A
100
−24.495
22.186
10.990
1.00
31.73
O
ATOM
131
N
ASP
A
101
−25.459
21.277
9.193
1.00
30.35
N
ATOM
132
CA
ASP
A
101
−24.662
20.072
9.267
1.00
30.10
C
ATOM
133
CB
ASP
A
101
−25.502
18.809
9.060
1.00
30.91
C
ATOM
134
CG
ASP
A
101
−26.681
18.707
10.025
1.00
31.96
C
ATOM
135
OD1
ASP
A
101
−26.458
18.846
11.256
1.00
33.73
O
ATOM
136
OD2
ASP
A
101
−27.815
18.479
9.538
1.00
31.46
O
ATOM
137
C
ASP
A
101
−23.617
20.188
8.171
1.00
29.73
C
ATOM
138
O
ASP
A
101
−23.823
20.894
7.189
1.00
30.58
O
ATOM
139
N
TRP
A
102
−22.472
19.540
8.345
1.00
29.30
N
ATOM
140
CA
TRP
A
102
−21.402
19.662
7.352
1.00
26.90
C
ATOM
141
CB
TRP
A
102
−20.371
20.709
7.759
1.00
27.28
C
ATOM
142
CG
TRP
A
102
−19.709
20.410
9.076
1.00
26.50
C
ATOM
143
CD1
TRP
A
102
−20.266
20.538
10.322
1.00
28.05
C
ATOM
144
NE1
TRP
A
102
−19.366
20.185
11.298
1.00
25.18
N
ATOM
145
CE2
TRP
A
102
−18.179
19.851
10.700
1.00
27.63
C
ATOM
146
CD2
TRP
A
102
−18.363
19.979
9.285
1.00
27.61
C
ATOM
147
CE3
TRP
A
102
−17.290
19.692
8.432
1.00
24.42
C
ATOM
148
CZ3
TRP
A
102
−16.064
19.254
9.001
1.00
24.78
C
ATOM
149
CH2
TRP
A
102
−15.922
19.115
10.407
1.00
27.13
C
ATOM
150
CZ2
TRP
A
102
−16.979
19.406
11.266
1.00
27.85
C
ATOM
151
C
TRP
A
102
−20.799
18.285
7.086
1.00
27.67
C
ATOM
152
O
TRP
A
102
−21.014
17.347
7.844
1.00
26.73
O
ATOM
153
N
PHE
A
103
−20.040
18.169
5.999
1.00
27.38
N
ATOM
154
CA
PHE
A
103
−19.555
16.865
5.544
1.00
26.65
C
ATOM
155
CB
PHE
A
103
−20.066
16.694
4.095
1.00
27.13
C
ATOM
156
CG
PHE
A
103
−19.353
15.647
3.275
1.00
29.74
C
ATOM
157
CD1
PHE
A
103
−19.838
14.339
3.223
1.00
32.10
C
ATOM
158
CE1
PHE
A
103
−19.198
13.365
2.419
1.00
29.36
C
ATOM
159
CZ
PHE
A
103
−18.095
13.730
1.649
1.00
31.44
C
ATOM
160
CE2
PHE
A
103
−17.614
15.036
1.668
1.00
34.30
C
ATOM
161
CD2
PHE
A
103
−18.245
15.993
2.478
1.00
33.21
C
ATOM
162
C
PHE
A
103
−18.031
16.886
5.539
1.00
25.08
C
ATOM
163
O
PHE
A
103
−17.427
17.901
5.181
1.00
25.47
O
ATOM
164
N
MET
A
104
−17.418
15.781
5.953
1.00
24.11
N
ATOM
165
CA
MET
A
104
−15.946
15.601
5.888
1.00
24.78
C
ATOM
166
CB
MET
A
104
−15.339
15.135
7.242
1.00
23.15
C
ATOM
167
CG
MET
A
104
−15.578
16.116
8.425
1.00
25.55
C
ATOM
168
SD
MET
A
104
−15.331
15.278
10.011
1.00
27.07
S
ATOM
169
CE
MET
A
104
−16.966
14.670
10.253
1.00
27.39
C
ATOM
170
C
MET
A
104
−15.672
14.532
4.832
1.00
24.85
C
ATOM
171
O
MET
A
104
−16.247
13.450
4.874
1.00
25.29
O
ATOM
172
N
LEU
A
105
−14.780
14.842
3.893
1.00
25.30
N
ATOM
173
CA
LEU
A
105
−14.315
13.870
2.911
1.00
24.88
C
ATOM
174
CB
LEU
A
105
−13.577
14.626
1.795
1.00
24.53
C
ATOM
175
CG
LEU
A
105
−13.109
13.799
0.593
1.00
30.23
C
ATOM
176
CD1
LEU
A
105
−14.315
13.128
−0.104
1.00
27.68
C
ATOM
177
CD2
LEU
A
105
−12.328
14.697
−0.333
1.00
31.62
C
ATOM
178
C
LEU
A
105
−13.473
12.817
3.534
1.00
24.44
C
ATOM
179
O
LEU
A
105
−13.600
11.624
3.187
1.00
25.09
O
ATOM
180
N
MET
A
106
−12.600
13.229
4.472
1.00
23.86
N
ATOM
181
CA
MET
A
106
−11.733
12.325
5.187
1.00
23.48
C
ATOM
182
CB
MET
A
106
−10.253
12.672
4.853
1.00
23.02
C
ATOM
183
CG
MET
A
106
−9.897
12.294
3.344
1.00
25.01
C
ATOM
184
SD
MET
A
106
−8.226
12.780
2.955
1.00
24.98
S
ATOM
185
CE
MET
A
106
−8.504
13.050
1.171
1.00
33.15
C
ATOM
186
C
MET
A
106
−11.987
12.547
6.702
1.00
24.02
C
ATOM
187
O
MET
A
106
−11.212
13.271
7.351
1.00
22.17
O
ATOM
188
N
PRO
A
107
−13.070
11.957
7.235
1.00
25.50
N
ATOM
189
CA
PRO
A
107
−13.453
12.363
8.597
1.00
25.66
C
ATOM
190
CB
PRO
A
107
−14.813
11.708
8.812
1.00
26.36
C
ATOM
191
CG
PRO
A
107
−15.014
10.716
7.645
1.00
27.67
C
ATOM
192
CD
PRO
A
107
−13.963
10.924
6.649
1.00
26.26
C
ATOM
193
C
PRO
A
107
−12.456
11.954
9.666
1.00
26.62
C
ATOM
194
O
PRO
A
107
−11.874
10.860
9.627
1.00
25.19
O
ATOM
195
N
LYS
A
108
−12.231
12.859
10.610
1.00
27.63
N
ATOM
196
CA
LYS
A
108
−11.452
12.532
11.791
1.00
26.56
C
ATOM
197
CB
LYS
A
108
−10.124
13.291
11.818
1.00
27.79
C
ATOM
198
CG
LYS
A
108
−9.108
13.047
10.659
1.00
28.05
C
ATOM
199
CD
LYS
A
108
−8.192
11.916
10.934
1.00
31.20
C
ATOM
200
CE
LYS
A
108
−8.719
10.611
10.548
1.00
30.45
C
ATOM
201
NZ
LYS
A
108
−8.945
10.441
9.045
1.00
33.91
N
ATOM
202
C
LYS
A
108
−12.304
13.026
12.953
1.00
27.72
C
ATOM
203
O
LYS
A
108
−12.825
14.177
12.935
1.00
24.97
O
ATOM
204
N
GLN
A
109
−12.403
12.194
13.977
1.00
27.58
N
ATOM
205
CA
GLN
A
109
−13.182
12.573
15.157
1.00
30.64
C
ATOM
206
CB
GLN
A
109
−14.621
12.111
15.006
1.00
29.87
C
ATOM
207
CG
GLN
A
109
−15.459
12.288
16.241
1.00
39.27
C
ATOM
208
CD
GLN
A
109
−16.683
11.376
16.235
1.00
46.13
C
ATOM
209
OE1
GLN
A
109
−16.724
10.376
16.970
1.00
48.01
O
ATOM
210
NE2
GLN
A
109
−17.666
11.693
15.375
1.00
46.81
N
ATOM
211
C
GLN
A
109
−12.504
11.988
16.372
1.00
30.84
C
ATOM
212
O
GLN
A
109
−12.006
10.853
16.332
1.00
31.32
O
ATOM
213
N
LYS
A
110
−12.372
12.810
17.404
1.00
30.66
N
ATOM
214
CA
LYS
A
110
−11.746
12.430
18.662
1.00
33.30
C
ATOM
215
CB
LYS
A
110
−10.384
13.105
18.838
1.00
32.59
C
ATOM
216
CG
LYS
A
110
−9.599
12.479
19.944
1.00
39.86
C
ATOM
217
CD
LYS
A
110
−8.308
13.201
20.198
1.00
44.72
C
ATOM
218
CE
LYS
A
110
−7.424
12.330
21.064
1.00
49.17
C
ATOM
219
NZ
LYS
A
110
−5.981
12.798
21.028
1.00
51.75
N
ATOM
220
C
LYS
A
110
−12.641
12.944
19.806
1.00
33.85
C
ATOM
221
O
LYS
A
110
−13.014
14.135
19.846
1.00
32.23
O
ATOM
222
N
VAL
A
111
−12.953
12.046
20.738
1.00
34.29
N
ATOM
223
CA
VAL
A
111
−13.601
12.447
21.969
1.00
35.38
C
ATOM
224
CB
VAL
A
111
−14.656
11.399
22.405
1.00
35.08
C
ATOM
225
CG1
VAL
A
111
−15.253
11.774
23.720
1.00
36.51
C
ATOM
226
CG2
VAL
A
111
−15.780
11.326
21.306
1.00
34.54
C
ATOM
227
C
VAL
A
111
−12.464
12.658
22.927
1.00
36.40
C
ATOM
228
O
VAL
A
111
−11.677
11.747
23.143
1.00
37.57
O
ATOM
229
N
GLU
A
112
−12.287
13.899
23.387
1.00
36.90
N
ATOM
230
CA
GLU
A
112
−11.288
14.204
24.400
1.00
38.96
C
ATOM
231
CB
GLU
A
112
−10.265
15.217
23.913
1.00
39.19
C
ATOM
232
CG
GLU
A
112
−9.175
14.530
23.156
1.00
46.21
C
ATOM
233
CD
GLU
A
112
−7.912
15.349
22.990
1.00
51.55
C
ATOM
234
OE1
GLU
A
112
−7.283
15.197
21.928
1.00
53.26
O
ATOM
235
OE2
GLU
A
112
−7.547
16.134
23.906
1.00
56.88
O
ATOM
236
C
GLU
A
112
−12.007
14.718
25.634
1.00
38.39
C
ATOM
237
O
GLU
A
112
−12.469
15.865
25.685
1.00
36.96
O
ATOM
238
N
GLY
A
113
−12.140
13.822
26.601
1.00
39.27
N
ATOM
239
CA
GLY
A
113
−12.917
14.119
27.796
1.00
38.12
C
ATOM
240
C
GLY
A
113
−14.353
14.437
27.464
1.00
36.64
C
ATOM
241
O
GLY
A
113
−15.033
13.655
26.776
1.00
38.16
O
ATOM
242
N
PRO
A
114
−14.849
15.576
27.964
1.00
33.88
N
ATOM
243
CA
PRO
A
114
−16.237
15.943
27.762
1.00
32.13
C
ATOM
244
CB
PRO
A
114
−16.492
16.931
28.916
1.00
32.60
C
ATOM
245
CG
PRO
A
114
−15.165
17.627
29.055
1.00
31.81
C
ATOM
246
CD
PRO
A
114
−14.126
16.576
28.781
1.00
34.84
C
ATOM
247
C
PRO
A
114
−16.509
16.645
26.405
1.00
29.72
C
ATOM
248
O
PRO
A
114
−17.657
17.067
26.146
1.00
28.42
O
ATOM
249
N
LEU
A
115
−15.499
16.717
25.536
1.00
28.35
N
ATOM
250
CA
LEU
A
115
−15.700
17.376
24.223
1.00
27.24
C
ATOM
251
CB
LEU
A
115
−14.794
18.599
24.129
1.00
27.96
C
ATOM
252
CG
LEU
A
115
−14.946
19.667
25.243
1.00
26.94
C
ATOM
253
CD1
LEU
A
115
−13.750
20.612
25.196
1.00
27.95
C
ATOM
254
CD2
LEU
A
115
−16.251
20.417
25.099
1.00
29.72
C
ATOM
255
C
LEU
A
115
−15.357
16.470
23.033
1.00
27.21
C
ATOM
256
O
LEU
A
115
−14.434
15.672
23.116
1.00
27.09
O
ATOM
257
N
CYS
A
116
−16.031
16.713
21.914
1.00
27.45
N
ATOM
258
CA
CYS
A
116
−15.783
15.992
20.659
1.00
26.39
C
ATOM
259
CB
CYS
A
116
−17.108
15.497
20.090
1.00
26.69
C
ATOM
260
SG
CYS
A
116
−16.868
14.551
18.501
1.00
31.80
S
ATOM
261
C
CYS
A
116
−15.120
16.929
19.656
1.00
25.74
C
ATOM
262
O
CYS
A
116
−15.639
18.029
19.409
1.00
25.83
O
ATOM
263
N
ILE
A
117
−13.960
16.523
19.126
1.00
24.09
N
ATOM
264
CA
ILE
A
117
−13.283
17.265
18.048
1.00
24.27
C
ATOM
265
CB
ILE
A
117
−11.755
17.349
18.356
1.00
25.27
C
ATOM
266
CG1
ILE
A
117
−11.517
17.862
19.806
1.00
23.31
C
ATOM
267
CD1
ILE
A
117
−10.154
17.452
20.379
1.00
26.08
C
ATOM
268
CG2
ILE
A
117
−11.015
18.197
17.315
1.00
22.67
C
ATOM
269
C
ILE
A
117
−13.472
16.573
16.692
1.00
23.94
C
ATOM
270
O
ILE
A
117
−13.241
15.340
16.562
1.00
23.40
O
ATOM
271
N
ARG
A
118
−13.839
17.358
15.693
1.00
22.86
N
ATOM
272
CA
ARG
A
118
−13.972
16.851
14.336
1.00
23.41
C
ATOM
273
CB
ARG
A
118
−15.425
16.931
13.889
1.00
24.33
C
ATOM
274
CG
ARG
A
118
−16.195
15.760
14.310
1.00
26.67
C
ATOM
275
CD
ARG
A
118
−17.648
16.145
14.171
1.00
36.06
C
ATOM
276
NE
ARG
A
118
−18.440
15.040
14.612
1.00
41.48
N
ATOM
277
CZ
ARG
A
118
−19.612
15.131
15.215
1.00
45.56
C
ATOM
278
NH1
ARG
A
118
−20.146
16.313
15.465
1.00
46.68
N
ATOM
279
NH2
ARG
A
118
−20.228
14.012
15.596
1.00
45.78
N
ATOM
280
C
ARG
A
118
−13.198
17.713
13.379
1.00
23.69
C
ATOM
281
O
ARG
A
118
−13.212
18.954
13.476
1.00
22.65
O
ATOM
282
N
ILE
A
119
−12.562
17.060
12.409
1.00
23.73
N
ATOM
283
CA
ILE
A
119
−11.831
17.816
11.420
1.00
24.09
C
ATOM
284
CB
ILE
A
119
−10.412
18.129
11.928
1.00
24.22
C
ATOM
285
CG1
ILE
A
119
−9.636
18.940
10.882
1.00
26.11
C
ATOM
286
CD1
ILE
A
119
−8.270
19.415
11.340
1.00
27.40
C
ATOM
287
CG2
ILE
A
119
−9.677
16.828
12.269
1.00
26.48
C
ATOM
288
C
ILE
A
119
−11.827
17.045
10.087
1.00
23.09
C
ATOM
289
O
ILE
A
119
−11.823
15.831
10.101
1.00
24.06
O
ATOM
290
N
ASP
A
120
−11.950
17.754
8.967
1.00
21.94
N
ATOM
291
CA
ASP
A
120
−11.754
17.122
7.654
1.00
21.86
C
ATOM
292
CB
ASP
A
120
−12.475
17.904
6.535
1.00
22.15
C
ATOM
293
CG
ASP
A
120
−12.612
17.057
5.250
1.00
23.64
C
ATOM
294
OD1
ASP
A
120
−11.983
15.954
5.179
1.00
24.29
O
ATOM
295
OD2
ASP
A
120
−13.343
17.458
4.348
1.00
23.75
O
ATOM
296
C
ASP
A
120
−10.269
17.079
7.331
1.00
21.18
C
ATOM
297
O
ASP
A
120
−9.679
18.112
7.116
1.00
21.54
O
ATOM
298
N
GLN
A
121
−9.681
15.887
7.316
1.00
21.00
N
ATOM
299
CA
GLN
A
121
−8.259
15.688
6.914
1.00
21.84
C
ATOM
300
CB
GLN
A
121
−7.873
14.225
7.121
1.00
22.28
C
ATOM
301
CG
GLN
A
121
−6.428
13.911
6.740
1.00
24.84
C
ATOM
302
CD
GLN
A
121
−5.968
12.511
7.069
1.00
25.52
C
ATOM
303
OE1
GLN
A
121
−6.754
11.585
7.276
1.00
23.53
O
ATOM
304
NE2
GLN
A
121
−4.627
12.340
7.096
1.00
25.16
N
ATOM
305
C
GLN
A
121
−7.981
16.150
5.467
1.00
22.62
C
ATOM
306
O
GLN
A
121
−6.829
16.437
5.080
1.00
21.93
O
ATOM
307
N
ALA
A
122
−9.054
16.261
4.685
1.00
21.71
N
ATOM
308
CA
ALA
A
122
−8.912
16.617
3.256
1.00
21.69
C
ATOM
309
CB
ALA
A
122
−10.181
16.141
2.494
1.00
19.71
C
ATOM
310
C
ALA
A
122
−8.662
18.107
3.052
1.00
22.50
C
ATOM
311
O
ALA
A
122
−8.187
18.546
1.985
1.00
23.74
O
ATOM
312
N
ILE
A
123
−8.969
18.924
4.058
1.00
22.64
N
ATOM
313
CA
ILE
A
123
−8.908
20.394
3.883
1.00
22.96
C
ATOM
314
CB
ILE
A
123
−9.911
21.109
4.803
1.00
23.42
C
ATOM
315
CG1
ILE
A
123
−11.364
20.728
4.413
1.00
24.78
C
ATOM
316
CD1
ILE
A
123
−11.800
21.234
3.011
1.00
28.40
C
ATOM
317
CG2
ILE
A
123
−9.756
22.634
4.681
1.00
22.20
C
ATOM
318
C
ILE
A
123
−7.508
20.981
4.108
1.00
25.70
C
ATOM
319
O
ILE
A
123
−6.947
20.792
5.178
1.00
25.29
O
ATOM
320
N
MET
A
124
−6.943
21.662
3.092
1.00
25.17
N
ATOM
321
CA
MET
A
124
−5.579
22.183
3.163
1.00
28.51
C
ATOM
322
CB
MET
A
124
−4.655
21.297
2.337
1.00
27.78
C
ATOM
323
CG
MET
A
124
−4.771
19.813
2.656
1.00
30.26
C
ATOM
324
SD
MET
A
124
−3.484
18.782
1.811
1.00
33.51
S
ATOM
325
CE
MET
A
124
−2.059
19.361
2.723
1.00
37.42
C
ATOM
326
C
MET
A
124
−5.578
23.562
2.553
1.00
28.55
C
ATOM
327
O
MET
A
124
−6.493
23.905
1.787
1.00
27.92
O
ATOM
328
N
ASP
A
125
−4.559
24.344
2.895
1.00
29.74
N
ATOM
329
CA
ASP
A
125
−4.215
25.614
2.253
1.00
32.07
C
ATOM
330
CB
ASP
A
125
−3.799
25.405
0.762
1.00
33.16
C
ATOM
331
CG
ASP
A
125
−2.736
24.338
0.604
1.00
35.13
C
ATOM
332
OD1
ASP
A
125
−1.696
24.451
1.278
1.00
36.19
O
ATOM
333
OD2
ASP
A
125
−2.941
23.385
−0.186
1.00
41.35
O
ATOM
334
C
ASP
A
125
−5.240
26.719
2.323
1.00
32.12
C
ATOM
335
O
ASP
A
125
−5.180
27.626
1.509
1.00
33.38
O
ATOM
336
N
LYS
A
126
−6.148
26.691
3.299
1.00
31.07
N
ATOM
337
CA
LYS
A
126
−7.178
27.720
3.386
1.00
30.62
C
ATOM
338
CB
LYS
A
126
−8.564
27.049
3.449
1.00
32.29
C
ATOM
339
CG
LYS
A
126
−8.996
26.577
2.028
1.00
35.51
C
ATOM
340
CD
LYS
A
126
−10.152
25.660
2.060
1.00
43.65
C
ATOM
341
CE
LYS
A
126
−10.660
25.433
0.631
1.00
44.47
C
ATOM
342
NZ
LYS
A
126
−11.170
26.689
−0.085
1.00
46.44
N
ATOM
343
C
LYS
A
126
−6.952
28.713
4.534
1.00
29.60
C
ATOM
344
O
LYS
A
126
−6.222
28.422
5.467
1.00
30.24
O
ATOM
345
N
ASN
A
127
−7.527
29.897
4.438
1.00
29.11
N
ATOM
346
CA
ASN
A
127
−7.523
30.805
5.578
1.00
29.06
C
ATOM
347
CB
ASN
A
127
−7.591
32.243
5.112
1.00
29.91
C
ATOM
348
CG
ASN
A
127
−6.308
32.677
4.437
1.00
33.89
C
ATOM
349
OD1
ASN
A
127
−5.214
32.543
4.998
1.00
36.73
O
ATOM
350
ND2
ASN
A
127
−6.427
33.183
3.229
1.00
37.36
N
ATOM
351
C
ASN
A
127
−8.789
30.387
6.358
1.00
28.50
C
ATOM
352
O
ASN
A
127
−9.860
30.326
5.787
1.00
26.56
O
ATOM
353
N
ILE
A
128
−8.625
30.078
7.639
1.00
27.29
N
ATOM
354
CA
ILE
A
128
−9.706
29.462
8.437
1.00
27.38
C
ATOM
355
CB
ILE
A
128
−9.295
28.032
8.952
1.00
27.42
C
ATOM
356
CG1
ILE
A
128
−9.024
27.037
7.799
1.00
27.03
C
ATOM
357
CD1
ILE
A
128
−10.184
26.824
6.863
1.00
28.44
C
ATOM
358
CG2
ILE
A
128
−10.342
27.441
9.962
1.00
26.81
C
ATOM
359
C
ILE
A
128
−9.957
30.371
9.641
1.00
27.01
C
ATOM
360
O
ILE
A
128
−9.014
30.865
10.239
1.00
27.70
O
ATOM
361
N
MET
A
129
−11.206
30.566
10.031
1.00
27.13
N
ATOM
362
CA
MET
A
129
−11.476
31.400
11.217
1.00
27.30
C
ATOM
363
CB
MET
A
129
−12.306
32.631
10.834
1.00
27.31
C
ATOM
364
CG
MET
A
129
−12.890
33.479
12.058
1.00
28.79
C
ATOM
365
SD
MET
A
129
−11.620
34.344
12.939
1.00
32.60
S
ATOM
366
CE
MET
A
129
−11.410
35.688
11.799
1.00
39.01
C
ATOM
367
C
MET
A
129
−12.264
30.526
12.183
1.00
26.82
C
ATOM
368
O
MET
A
129
−13.285
29.938
11.788
1.00
27.01
O
ATOM
369
N
LEU
A
130
−11.813
30.470
13.432
1.00
26.13
N
ATOM
370
CA
LEU
A
130
−12.575
29.765
14.497
1.00
26.12
C
ATOM
371
CB
LEU
A
130
−11.618
29.297
15.610
1.00
24.84
C
ATOM
372
CG
LEU
A
130
−10.485
28.337
15.243
1.00
27.14
C
ATOM
373
CD1
LEU
A
130
−10.087
27.626
16.479
1.00
22.57
C
ATOM
374
CD2
LEU
A
130
−10.891
27.282
14.117
1.00
22.23
C
ATOM
375
C
LEU
A
130
−13.601
30.733
15.080
1.00
25.81
C
ATOM
376
O
LEU
A
130
−13.231
31.837
15.498
1.00
26.04
O
ATOM
377
N
LYS
A
131
−14.873
30.330
15.076
1.00
26.76
N
ATOM
378
CA
LYS
A
131
−15.956
31.068
15.722
1.00
26.56
C
ATOM
379
CB
LYS
A
131
−17.004
31.490
14.684
1.00
27.61
C
ATOM
380
CG
LYS
A
131
−16.533
32.568
13.680
1.00
28.89
C
ATOM
381
CD
LYS
A
131
−17.691
32.884
12.680
1.00
28.82
C
ATOM
382
CE
LYS
A
131
−17.415
34.227
12.031
1.00
38.35
C
ATOM
383
NZ
LYS
A
131
−18.327
34.532
10.898
1.00
41.90
N
ATOM
384
C
LYS
A
131
−16.645
30.157
16.768
1.00
26.72
C
ATOM
385
O
LYS
A
131
−16.730
28.927
16.598
1.00
24.29
O
ATOM
386
N
ALA
A
132
−17.188
30.754
17.832
1.00
24.37
N
ATOM
387
CA
ALA
A
132
−17.802
29.955
18.881
1.00
23.81
C
ATOM
388
CB
ALA
A
132
−16.725
29.487
19.941
1.00
23.01
C
ATOM
389
C
ALA
A
132
−18.968
30.664
19.540
1.00
24.34
C
ATOM
390
O
ALA
A
132
−19.104
31.907
19.494
1.00
24.27
O
ATOM
391
N
ASN
A
133
−19.845
29.844
20.107
1.00
24.68
N
ATOM
392
CA
ASN
A
133
−20.919
30.315
20.981
1.00
24.43
C
ATOM
393
CB
ASN
A
133
−22.314
29.912
20.475
1.00
23.91
C
ATOM
394
CG
ASN
A
133
−22.739
30.645
19.185
1.00
27.90
C
ATOM
395
OD1
ASN
A
133
−21.937
31.202
18.437
1.00
29.10
O
ATOM
396
ND2
ASN
A
133
−24.037
30.641
18.941
1.00
29.92
N
ATOM
397
C
ASN
A
133
−20.631
29.666
22.321
1.00
23.54
C
ATOM
398
O
ASN
A
133
−20.369
28.458
22.420
1.00
21.57
O
ATOM
399
N
PHE
A
134
−20.630
30.478
23.364
1.00
23.58
N
ATOM
400
CA
PHE
A
134
−20.216
30.016
24.672
1.00
23.28
C
ATOM
401
CB
PHE
A
134
−18.686
29.889
24.725
1.00
23.19
C
ATOM
402
CG
PHE
A
134
−17.902
31.138
24.314
1.00
24.74
C
ATOM
403
CD1
PHE
A
134
−17.415
32.026
25.291
1.00
24.85
C
ATOM
404
CE1
PHE
A
134
−16.650
33.169
24.927
1.00
26.78
C
ATOM
405
CZ
PHE
A
134
−16.343
33.397
23.561
1.00
24.67
C
ATOM
406
CE2
PHE
A
134
−16.823
32.475
22.585
1.00
25.59
C
ATOM
407
CD2
PHE
A
134
−17.603
31.398
22.973
1.00
22.93
C
ATOM
408
C
PHE
A
134
−20.692
30.994
25.723
1.00
25.08
C
ATOM
409
O
PHE
A
134
−20.852
32.198
25.446
1.00
24.04
O
ATOM
410
N
SER
A
135
−20.907
30.505
26.947
1.00
27.07
N
ATOM
411
CA
SER
A
135
−21.114
31.469
28.052
1.00
27.47
C
ATOM
412
CB
SER
A
135
−22.052
30.866
29.115
1.00
28.10
C
ATOM
413
OG
SER
A
135
−21.485
29.691
29.625
1.00
27.20
O
ATOM
414
C
SER
A
135
−19.779
31.893
28.672
1.00
28.03
C
ATOM
415
O
SER
A
135
−18.787
31.176
28.560
1.00
27.68
O
ATOM
416
N
VAL
A
136
−19.759
33.076
29.322
1.00
27.28
N
ATOM
417
CA
VAL
A
136
−18.598
33.610
29.998
1.00
27.41
C
ATOM
418
CB
VAL
A
136
−18.080
34.893
29.301
1.00
27.85
C
ATOM
419
CG1
VAL
A
136
−17.743
34.601
27.826
1.00
26.37
C
ATOM
420
CG2
VAL
A
136
−19.146
35.948
29.291
1.00
28.25
C
ATOM
421
C
VAL
A
136
−18.984
33.932
31.476
1.00
27.55
C
ATOM
422
O
VAL
A
136
−20.127
34.219
31.766
1.00
28.10
O
ATOM
423
N
ILE
A
137
−18.023
33.867
32.365
1.00
28.59
N
ATOM
424
CA
ILE
A
137
−18.216
34.244
33.773
1.00
30.78
C
ATOM
425
CB
ILE
A
137
−18.669
32.988
34.633
1.00
31.59
C
ATOM
426
CG1
ILE
A
137
−19.278
33.429
35.970
1.00
33.63
C
ATOM
427
CD1
ILE
A
137
−19.700
32.180
36.817
1.00
33.97
C
ATOM
428
CG2
ILE
A
137
−17.505
31.987
34.863
1.00
30.94
C
ATOM
429
C
ILE
A
137
−16.849
34.653
34.155
1.00
29.64
C
ATOM
430
O
ILE
A
137
−15.907
34.068
33.633
1.00
29.94
O
ATOM
431
N
PHE
A
138
−16.694
35.682
35.016
1.00
29.62
N
ATOM
432
CA
PHE
A
138
−15.376
36.106
35.473
1.00
27.79
C
ATOM
433
CB
PHE
A
138
−14.703
35.101
36.440
1.00
28.87
C
ATOM
434
CG
PHE
A
138
−15.633
34.568
37.491
1.00
31.41
C
ATOM
435
CD1
PHE
A
138
−15.510
33.255
37.960
1.00
33.05
C
ATOM
436
CE1
PHE
A
138
−16.400
32.772
38.924
1.00
32.87
C
ATOM
437
CZ
PHE
A
138
−17.415
33.603
39.441
1.00
32.93
C
ATOM
438
CE2
PHE
A
138
−17.535
34.898
38.987
1.00
32.39
C
ATOM
439
CD2
PHE
A
138
−16.637
35.374
38.008
1.00
31.10
C
ATOM
440
C
PHE
A
138
−14.432
36.427
34.313
1.00
27.04
C
ATOM
441
O
PHE
A
138
−13.237
36.182
34.391
1.00
26.40
O
ATOM
442
N
ASP
A
139
−14.950
37.048
33.271
1.00
27.25
N
ATOM
443
CA
ASP
A
139
−14.059
37.476
32.165
1.00
28.11
C
ATOM
444
CB
ASP
A
139
−12.995
38.467
32.686
1.00
26.07
C
ATOM
445
CG
ASP
A
139
−12.315
39.241
31.545
1.00
24.48
C
ATOM
446
OD1
ASP
A
139
−13.054
39.624
30.621
1.00
23.66
O
ATOM
447
OD2
ASP
A
139
−11.077
39.441
31.582
0.50
20.56
O
ATOM
448
C
ASP
A
139
−13.343
36.319
31.435
1.00
28.35
C
ATOM
449
O
ASP
A
139
−12.247
36.500
30.876
1.00
29.04
O
ATOM
450
N
ARG
A
140
−13.949
35.142
31.450
1.00
28.71
N
ATOM
451
CA
ARG
A
140
−13.370
33.986
30.757
1.00
30.54
C
ATOM
452
CB
ARG
A
140
−12.409
33.226
31.674
1.00
31.65
C
ATOM
453
CG
ARG
A
140
−13.182
32.536
32.786
1.00
35.69
C
ATOM
454
CD
ARG
A
140
−12.363
31.446
33.453
1.00
41.63
C
ATOM
455
NE
ARG
A
140
−12.991
31.094
34.722
1.00
45.91
N
ATOM
456
CZ
ARG
A
140
−13.998
30.238
34.861
1.00
49.56
C
ATOM
457
NH1
ARG
A
140
−14.524
29.612
33.793
1.00
48.61
N
ATOM
458
NH2
ARG
A
140
−14.475
30.001
36.082
1.00
49.00
N
ATOM
459
C
ARG
A
140
−14.482
33.073
30.279
1.00
29.51
C
ATOM
460
O
ARG
A
140
−15.596
33.103
30.785
1.00
30.10
O
ATOM
461
N
LEU
A
141
−14.182
32.268
29.264
1.00
30.56
N
ATOM
462
CA
LEU
A
141
−15.155
31.290
28.753
1.00
29.62
C
ATOM
463
CB
LEU
A
141
−14.496
30.410
27.659
1.00
29.02
C
ATOM
464
CG
LEU
A
141
−15.359
29.328
27.005
1.00
30.21
C
ATOM
465
CD1
LEU
A
141
−14.998
29.213
25.514
1.00
25.61
C
ATOM
466
CD2
LEU
A
141
−15.146
27.989
27.689
1.00
28.22
C
ATOM
467
C
LEU
A
141
−15.579
30.396
29.907
1.00
29.31
C
ATOM
468
O
LEU
A
141
−14.754
29.975
30.687
1.00
29.67
O
ATOM
469
N
GLU
A
142
−16.862
30.108
29.994
1.00
28.07
N
ATOM
470
CA
GLU
A
142
−17.352
29.241
31.047
1.00
28.71
C
ATOM
471
CB
GLU
A
142
−18.590
29.848
31.667
1.00
29.55
C
ATOM
472
CG
GLU
A
142
−19.167
28.964
32.766
1.00
32.35
C
ATOM
473
CD
GLU
A
142
−20.382
29.575
33.338
1.00
38.85
C
ATOM
474
OE1
GLU
A
142
−20.438
29.665
34.586
1.00
43.19
O
ATOM
475
OE2
GLU
A
142
−21.250
30.017
32.550
1.00
42.00
O
ATOM
476
C
GLU
A
142
−17.759
27.888
30.468
1.00
27.92
C
ATOM
477
O
GLU
A
142
−17.164
26.875
30.802
1.00
28.27
O
ATOM
478
N
THR
A
143
−18.763
27.910
29.593
1.00
27.95
N
ATOM
479
CA
THR
A
143
−19.305
26.688
28.986
1.00
28.53
C
ATOM
480
CB
THR
A
143
−20.710
26.388
29.572
1.00
28.46
C
ATOM
481
OG1
THR
A
143
−20.565
26.177
30.990
1.00
30.36
O
ATOM
482
CG2
THR
A
143
−21.331
25.138
28.946
1.00
32.14
C
ATOM
483
C
THR
A
143
−19.370
26.837
27.462
1.00
27.05
C
ATOM
484
O
THR
A
143
−20.027
27.702
26.949
1.00
28.79
O
ATOM
485
N
LEU
A
144
−18.719
25.950
26.736
1.00
26.74
N
ATOM
486
CA
LEU
A
144
−18.790
25.988
25.263
1.00
23.71
C
ATOM
487
CB
LEU
A
144
−17.608
25.189
24.712
1.00
23.74
C
ATOM
488
CG
LEU
A
144
−17.563
25.142
23.164
1.00
23.31
C
ATOM
489
CD1
LEU
A
144
−17.213
26.514
22.590
1.00
23.32
C
ATOM
490
CD2
LEU
A
144
−16.567
24.119
22.730
1.00
22.22
C
ATOM
491
C
LEU
A
144
−20.119
25.426
24.797
1.00
24.71
C
ATOM
492
O
LEU
A
144
−20.529
24.338
25.242
1.00
24.35
O
ATOM
493
N
ILE
A
145
−20.821
26.133
23.923
1.00
23.45
N
ATOM
494
CA
ILE
A
145
−21.970
25.538
23.265
1.00
25.19
C
ATOM
495
CB
ILE
A
145
−23.055
26.592
23.018
1.00
25.84
C
ATOM
496
CG1
ILE
A
145
−23.640
27.052
24.388
1.00
30.13
C
ATOM
497
CD1
ILE
A
145
−24.255
28.496
24.272
1.00
38.82
C
ATOM
498
CG2
ILE
A
145
−24.150
26.089
22.057
1.00
26.97
C
ATOM
499
C
ILE
A
145
−21.515
24.854
21.938
1.00
25.87
C
ATOM
500
O
ILE
A
145
−21.817
23.679
21.687
1.00
23.59
O
ATOM
501
N
LEU
A
146
−20.772
25.593
21.112
1.00
25.26
N
ATOM
502
CA
LEU
A
146
−20.211
24.985
19.893
1.00
23.95
C
ATOM
503
CB
LEU
A
146
−21.302
24.942
18.833
1.00
23.73
C
ATOM
504
CG
LEU
A
146
−21.016
24.183
17.505
1.00
24.90
C
ATOM
505
CD1
LEU
A
146
−20.763
22.691
17.791
1.00
25.12
C
ATOM
506
CD2
LEU
A
146
−22.185
24.339
16.580
1.00
24.67
C
ATOM
507
C
LEU
A
146
−19.118
25.874
19.383
1.00
23.11
C
ATOM
508
O
LEU
A
146
−19.292
27.130
19.424
1.00
22.17
O
ATOM
509
N
LEU
A
147
−18.034
25.281
18.835
1.00
22.70
N
ATOM
510
CA
LEU
A
147
−17.008
26.058
18.122
1.00
21.78
C
ATOM
511
CB
LEU
A
147
−15.647
25.947
18.857
1.00
22.68
C
ATOM
512
CG
LEU
A
147
−14.450
26.653
18.206
1.00
22.20
C
ATOM
513
CD1
LEU
A
147
−13.385
27.062
19.271
1.00
20.77
C
ATOM
514
CD2
LEU
A
147
−13.814
25.775
17.088
1.00
19.37
C
ATOM
515
C
LEU
A
147
−16.907
25.455
16.717
1.00
22.57
C
ATOM
516
O
LEU
A
147
−16.910
24.212
16.593
1.00
20.70
O
ATOM
517
N
ARG
A
148
−16.848
26.293
15.663
1.00
22.59
N
ATOM
518
CA
ARG
A
148
−16.671
25.730
14.283
1.00
23.35
C
ATOM
519
CB
ARG
A
148
−17.969
25.749
13.455
1.00
22.58
C
ATOM
520
CG
ARG
A
148
−18.861
24.593
13.818
1.00
23.66
C
ATOM
521
CD
ARG
A
148
−20.240
24.671
13.269
1.00
23.87
C
ATOM
522
NE
ARG
A
148
−20.804
23.336
13.367
1.00
23.59
N
ATOM
523
CZ
ARG
A
148
−22.035
22.980
12.978
1.00
25.11
C
ATOM
524
NH1
ARG
A
148
−22.902
23.870
12.516
1.00
22.41
N
ATOM
525
NH2
ARG
A
148
−22.395
21.722
13.079
1.00
22.69
N
ATOM
526
C
ARG
A
148
−15.582
26.490
13.594
1.00
23.50
C
ATOM
527
O
ARG
A
148
−15.329
27.665
13.935
1.00
23.78
O
ATOM
528
N
ALA
A
149
−14.904
25.785
12.696
1.00
23.63
N
ATOM
529
CA
ALA
A
149
−13.834
26.339
11.887
1.00
22.68
C
ATOM
530
CB
ALA
A
149
−12.672
25.334
11.840
1.00
21.04
C
ATOM
531
C
ALA
A
149
−14.403
26.626
10.477
1.00
23.39
C
ATOM
532
O
ALA
A
149
−14.904
25.710
9.830
1.00
22.23
O
ATOM
533
N
PHE
A
150
−14.330
27.903
10.033
1.00
23.42
N
ATOM
534
CA
PHE
A
150
−14.947
28.333
8.761
1.00
24.77
C
ATOM
535
CB
PHE
A
150
−15.867
29.532
9.015
1.00
24.60
C
ATOM
536
CG
PHE
A
150
−17.135
29.184
9.792
1.00
26.17
C
ATOM
537
CD1
PHE
A
150
−17.133
29.193
11.188
1.00
25.87
C
ATOM
538
CE1
PHE
A
150
−18.268
28.861
11.919
1.00
27.48
C
ATOM
539
CZ
PHE
A
150
−19.440
28.542
11.266
1.00
25.00
C
ATOM
540
CE2
PHE
A
150
−19.474
28.526
9.862
1.00
26.61
C
ATOM
541
CD2
PHE
A
150
−18.288
28.825
9.124
1.00
25.13
C
ATOM
542
C
PHE
A
150
−13.895
28.796
7.717
1.00
24.98
C
ATOM
543
O
PHE
A
150
−12.963
29.457
8.072
1.00
24.09
O
ATOM
544
N
THR
A
151
−14.067
28.444
6.438
1.00
27.78
N
ATOM
545
CA
THR
A
151
−13.220
28.983
5.382
1.00
29.28
C
ATOM
546
CB
THR
A
151
−13.312
28.158
4.077
1.00
28.87
C
ATOM
547
OG1
THR
A
151
−14.613
28.302
3.542
1.00
29.93
O
ATOM
548
CG2
THR
A
151
−13.106
26.674
4.323
1.00
29.18
C
ATOM
549
C
THR
A
151
−13.743
30.414
5.115
1.00
31.10
C
ATOM
550
O
THR
A
151
−14.779
30.810
5.628
1.00
29.33
O
ATOM
551
N
GLU
A
152
−13.033
31.168
4.282
1.00
33.68
N
ATOM
552
CA
GLU
A
152
−13.425
32.530
3.902
1.00
36.84
C
ATOM
553
CB
GLU
A
152
−12.347
33.131
2.999
1.00
37.30
C
ATOM
554
CG
GLU
A
152
−11.005
33.248
3.642
1.00
39.17
C
ATOM
555
CD
GLU
A
152
−10.026
34.031
2.777
1.00
48.59
C
ATOM
556
OE1
GLU
A
152
−9.561
33.489
1.748
1.00
51.49
O
ATOM
557
OE2
GLU
A
152
−9.735
35.191
3.123
1.00
49.86
O
ATOM
558
C
GLU
A
152
−14.765
32.567
3.170
1.00
37.80
C
ATOM
559
O
GLU
A
152
−15.468
33.595
3.173
1.00
39.18
O
ATOM
560
N
GLU
A
153
−15.098
31.444
2.547
1.00
38.19
N
ATOM
561
CA
GLU
A
153
−16.337
31.296
1.834
1.00
39.91
C
ATOM
562
CB
GLU
A
153
−16.145
30.349
0.633
1.00
41.25
C
ATOM
563
CG
GLU
A
153
−15.204
30.939
−0.498
1.00
47.72
C
ATOM
564
CD
GLU
A
153
−15.857
32.067
−1.366
1.00
56.46
C
ATOM
565
OE1
GLU
A
153
−17.009
32.489
−1.073
1.00
59.59
O
ATOM
566
OE2
GLU
A
153
−15.213
32.532
−2.361
1.00
59.71
O
ATOM
567
C
GLU
A
153
−17.466
30.825
2.747
1.00
39.18
C
ATOM
568
O
GLU
A
153
−18.595
30.594
2.283
1.00
40.28
O
ATOM
569
N
GLY
A
154
−17.183
30.645
4.037
1.00
36.32
N
ATOM
570
CA
GLY
A
154
−18.270
30.319
4.947
1.00
33.51
C
ATOM
571
C
GLY
A
154
−18.506
28.837
5.178
1.00
31.90
C
ATOM
572
O
GLY
A
154
−19.430
28.472
5.925
1.00
31.26
O
ATOM
573
N
ALA
A
155
−17.682
27.983
4.576
1.00
29.65
N
ATOM
574
CA
ALA
A
155
−17.837
26.524
4.714
1.00
28.90
C
ATOM
575
CB
ALA
A
155
−17.137
25.812
3.566
1.00
28.42
C
ATOM
576
C
ALA
A
155
−17.242
26.021
6.058
1.00
27.62
C
ATOM
577
O
ALA
A
155
−16.182
26.465
6.447
1.00
27.58
O
ATOM
578
N
ILE
A
156
−17.872
25.034
6.677
1.00
26.27
N
ATOM
579
CA
ILE
A
156
−17.329
24.438
7.943
1.00
25.83
C
ATOM
580
CB
ILE
A
156
−18.495
23.902
8.878
1.00
24.89
C
ATOM
581
CG1
ILE
A
156
−19.502
25.006
9.143
1.00
25.36
C
ATOM
582
CD1
ILE
A
156
−20.917
24.545
9.521
1.00
25.07
C
ATOM
583
CG2
ILE
A
156
−17.916
23.352
10.265
1.00
24.02
C
ATOM
584
C
ILE
A
156
−16.376
23.290
7.644
1.00
25.13
C
ATOM
585
O
ILE
A
156
−16.737
22.408
6.867
1.00
25.16
O
ATOM
586
N
VAL
A
157
−15.170
23.316
8.241
1.00
24.13
N
ATOM
587
CA
VAL
A
157
−14.131
22.283
8.038
1.00
24.32
C
ATOM
588
CB
VAL
A
157
−12.963
22.870
7.253
1.00
24.35
C
ATOM
589
CG1
VAL
A
157
−13.491
23.401
5.896
1.00
24.56
C
ATOM
590
CG2
VAL
A
157
−12.253
24.009
8.052
1.00
23.30
C
ATOM
591
C
VAL
A
157
−13.643
21.653
9.369
1.00
24.38
C
ATOM
592
O
VAL
A
157
−12.742
20.787
9.381
1.00
24.39
O
ATOM
593
N
GLY
A
158
−14.280
22.055
10.480
1.00
22.71
N
ATOM
594
CA
GLY
A
158
−13.817
21.558
11.800
1.00
22.42
C
ATOM
595
C
GLY
A
158
−14.768
22.001
12.869
1.00
22.76
C
ATOM
596
O
GLY
A
158
−15.476
22.988
12.689
1.00
22.09
O
ATOM
597
N
GLU
A
159
−14.778
21.272
13.985
1.00
22.77
N
ATOM
598
CA
GLU
A
159
−15.685
21.643
15.055
1.00
23.62
C
ATOM
599
CB
GLU
A
159
−17.076
21.080
14.702
1.00
23.86
C
ATOM
600
CG
GLU
A
159
−18.105
20.927
15.738
1.00
27.75
C
ATOM
601
CD
GLU
A
159
−19.298
20.220
15.110
1.00
30.96
C
ATOM
602
OE1
GLU
A
159
−19.649
19.085
15.511
1.00
33.41
O
ATOM
603
OE2
GLU
A
159
−19.793
20.784
14.126
1.00
31.84
O
ATOM
604
C
GLU
A
159
−15.224
21.096
16.400
1.00
23.45
C
ATOM
605
O
GLU
A
159
−14.503
20.083
16.451
1.00
23.41
O
ATOM
606
N
ILE
A
160
−15.623
21.803
17.461
1.00
21.90
N
ATOM
607
CA
ILE
A
160
−15.490
21.267
18.833
1.00
22.61
C
ATOM
608
CB
ILE
A
160
−14.472
21.994
19.660
1.00
22.90
C
ATOM
609
CG1
ILE
A
160
−13.072
21.846
19.064
1.00
20.56
C
ATOM
610
CD1
ILE
A
160
−12.068
22.911
19.659
1.00
23.51
C
ATOM
611
CG2
ILE
A
160
−14.473
21.422
21.160
1.00
20.30
C
ATOM
612
C
ILE
A
160
−16.868
21.407
19.432
1.00
23.34
C
ATOM
613
O
ILE
A
160
−17.471
22.524
19.438
1.00
21.20
O
ATOM
614
N
SER
A
161
−17.418
20.269
19.860
1.00
25.69
N
ATOM
615
CA
SER
A
161
−18.758
20.307
20.418
1.00
28.95
C
ATOM
616
CB
SER
A
161
−19.773
19.669
19.476
1.00
30.16
C
ATOM
617
OG
SER
A
161
−19.433
18.304
19.310
1.00
36.69
O
ATOM
618
C
SER
A
161
−18.770
19.573
21.739
1.00
31.31
C
ATOM
619
O
SER
A
161
−18.092
18.550
21.879
1.00
32.13
O
ATOM
620
N
PRO
A
162
−19.565
20.074
22.721
1.00
32.42
N
ATOM
621
CA
PRO
A
162
−19.717
19.308
23.967
1.00
32.99
C
ATOM
622
CB
PRO
A
162
−20.635
20.208
24.823
1.00
33.01
C
ATOM
623
CG
PRO
A
162
−21.460
21.013
23.754
1.00
34.38
C
ATOM
624
CD
PRO
A
162
−20.382
21.303
22.712
1.00
31.98
C
ATOM
625
C
PRO
A
162
−20.416
17.973
23.669
1.00
34.31
C
ATOM
626
O
PRO
A
162
−21.251
17.896
22.770
1.00
33.06
O
ATOM
627
N
LEU
A
163
−20.094
16.942
24.424
1.00
35.01
N
ATOM
628
CA
LEU
A
163
−20.872
15.726
24.360
1.00
39.63
C
ATOM
629
CB
LEU
A
163
−20.148
14.628
25.128
1.00
37.49
C
ATOM
630
CG
LEU
A
163
−18.770
14.289
24.594
1.00
38.56
C
ATOM
631
CD1
LEU
A
163
−18.110
13.411
25.596
1.00
42.42
C
ATOM
632
CD2
LEU
A
163
−18.870
13.613
23.197
1.00
37.70
C
ATOM
633
C
LEU
A
163
−22.287
15.986
24.964
1.00
43.24
C
ATOM
634
O
LEU
A
163
−22.429
16.761
25.922
1.00
42.85
O
ATOM
635
N
PRO
A
164
−23.329
15.347
24.407
1.00
47.70
N
ATOM
636
CA
PRO
A
164
−24.713
15.544
24.904
1.00
50.86
C
ATOM
637
CB
PRO
A
164
−25.488
14.431
24.216
1.00
50.96
C
ATOM
638
CG
PRO
A
164
−24.731
14.153
22.964
1.00
50.70
C
ATOM
639
CD
PRO
A
164
−23.272
14.390
23.288
1.00
48.08
C
ATOM
640
C
PRO
A
164
−24.778
15.330
26.404
1.00
53.85
C
ATOM
641
O
PRO
A
164
−25.371
16.133
27.144
1.00
55.14
O
ATOM
642
N
SER
A
165
−24.109
14.268
26.836
1.00
56.89
N
ATOM
643
CA
SER
A
165
−24.161
13.771
28.201
1.00
59.40
C
ATOM
644
CB
SER
A
165
−23.132
12.627
28.372
1.00
59.96
C
ATOM
645
OG
SER
A
165
−22.736
11.981
27.151
1.00
61.14
O
ATOM
646
C
SER
A
165
−23.886
14.862
29.261
1.00
60.68
C
ATOM
647
O
SER
A
165
−24.578
14.937
30.285
1.00
61.29
O
ATOM
648
N
PHE
A
166
−22.862
15.683
29.014
1.00
61.57
N
ATOM
649
CA
PHE
A
166
−22.397
16.669
29.980
1.00
61.86
C
ATOM
650
CB
PHE
A
166
−20.878
16.850
29.924
1.00
62.01
C
ATOM
651
CG
PHE
A
166
−20.108
15.569
29.780
1.00
62.40
C
ATOM
652
CD1
PHE
A
166
−19.110
15.241
30.690
1.00
63.33
C
ATOM
653
CE1
PHE
A
166
−18.373
14.035
30.563
1.00
65.13
C
ATOM
654
CZ
PHE
A
166
−18.651
13.167
29.514
1.00
64.22
C
ATOM
655
CE2
PHE
A
166
−19.666
13.493
28.597
1.00
64.14
C
ATOM
656
CD2
PHE
A
166
−20.371
14.691
28.729
1.00
62.88
C
ATOM
657
C
PHE
A
166
−23.042
18.021
29.748
1.00
62.36
C
ATOM
658
O
PHE
A
166
−23.417
18.368
28.598
1.00
62.89
O
ATOM
659
N
PRO
A
167
−23.210
18.775
30.845
1.00
62.06
N
ATOM
660
CA
PRO
A
167
−23.394
20.224
30.872
1.00
61.87
C
ATOM
661
CB
PRO
A
167
−24.570
20.379
31.857
1.00
61.66
C
ATOM
662
CG
PRO
A
167
−24.317
19.276
32.881
1.00
62.79
C
ATOM
663
CD
PRO
A
167
−23.353
18.232
32.208
1.00
62.77
C
ATOM
664
C
PRO
A
167
−22.130
20.921
31.431
1.00
60.38
C
ATOM
665
O
PRO
A
167
−22.154
22.141
31.695
1.00
61.90
O
ATOM
666
N
GLY
A
168
−21.050
20.148
31.606
1.00
57.49
N
ATOM
667
CA
GLY
A
168
−19.868
20.625
32.321
1.00
53.21
C
ATOM
668
C
GLY
A
168
−18.504
20.149
31.843
1.00
49.27
C
ATOM
669
O
GLY
A
168
−18.198
18.926
31.777
1.00
49.67
O
ATOM
670
N
HIS
A
169
−17.681
21.149
31.549
1.00
44.84
N
ATOM
671
CA
HIS
A
169
−16.297
20.976
31.148
1.00
40.46
C
ATOM
672
CB
HIS
A
169
−16.170
20.820
29.602
1.00
38.65
C
ATOM
673
CG
HIS
A
169
−16.962
21.841
28.822
1.00
33.52
C
ATOM
674
ND1
HIS
A
169
−18.188
21.564
28.261
1.00
31.35
N
ATOM
675
CE1
HIS
A
169
−18.660
22.637
27.660
1.00
28.39
C
ATOM
676
NE2
HIS
A
169
−17.796
23.616
27.828
1.00
28.28
N
ATOM
677
CD2
HIS
A
169
−16.724
23.149
28.553
1.00
30.88
C
ATOM
678
C
HIS
A
169
−15.680
22.280
31.615
1.00
39.31
C
ATOM
679
O
HIS
A
169
−16.410
23.196
32.044
1.00
40.25
O
ATOM
680
N
THR
A
170
−14.353
22.339
31.567
1.00
36.78
N
ATOM
681
CA
THR
A
170
−13.572
23.479
32.029
1.00
35.94
C
ATOM
682
CB
THR
A
170
−12.377
23.065
32.927
1.00
35.25
C
ATOM
683
OG1
THR
A
170
−11.388
22.393
32.139
1.00
34.72
O
ATOM
684
CG2
THR
A
170
−12.827
22.132
34.101
1.00
36.64
C
ATOM
685
C
THR
A
170
−13.000
24.216
30.823
1.00
35.21
C
ATOM
686
O
THR
A
170
−12.946
23.678
29.710
1.00
34.35
O
ATOM
687
N
ILE
A
171
−12.568
25.444
31.058
1.00
33.91
N
ATOM
688
CA
ILE
A
171
−11.914
26.233
30.027
1.00
33.18
C
ATOM
689
CB
ILE
A
171
−11.670
27.696
30.532
1.00
32.72
C
ATOM
690
CG1
ILE
A
171
−11.151
28.586
29.382
1.00
33.82
C
ATOM
691
CD1
ILE
A
171
−11.256
30.068
29.689
1.00
32.91
C
ATOM
692
CG2
ILE
A
171
−10.725
27.732
31.733
1.00
33.57
C
ATOM
693
C
ILE
A
171
−10.620
25.547
29.575
1.00
32.14
C
ATOM
694
O
ILE
A
171
−10.221
25.637
28.412
1.00
31.34
O
ATOM
695
N
GLU
A
172
−9.965
24.841
30.492
1.00
31.90
N
ATOM
696
CA
GLU
A
172
−8.761
24.099
30.150
1.00
32.76
C
ATOM
697
CB
GLU
A
172
−8.014
23.596
31.399
1.00
33.50
C
ATOM
698
CG
GLU
A
172
−7.752
24.691
32.487
1.00
38.99
C
ATOM
699
CD
GLU
A
172
−8.749
24.570
33.660
1.00
46.04
C
ATOM
700
OE1
GLU
A
172
−8.553
23.659
34.517
1.00
53.70
O
ATOM
701
OE2
GLU
A
172
−9.725
25.351
33.744
1.00
48.14
O
ATOM
702
C
GLU
A
172
−9.055
22.916
29.185
1.00
31.70
C
ATOM
703
O
GLU
A
172
−8.256
22.649
28.286
1.00
31.20
O
ATOM
704
N
ASP
A
173
−10.171
22.207
29.399
1.00
31.31
N
ATOM
705
CA
ASP
A
173
−10.650
21.204
28.408
1.00
30.63
C
ATOM
706
CB
ASP
A
173
−12.011
20.603
28.808
1.00
29.29
C
ATOM
707
CG
ASP
A
173
−11.929
19.745
30.069
1.00
32.36
C
ATOM
708
OD1
ASP
A
173
−10.912
19.089
30.317
1.00
36.48
O
ATOM
709
OD2
ASP
A
173
−12.885
19.746
30.820
1.00
29.46
O
ATOM
710
C
ASP
A
173
−10.859
21.898
27.049
1.00
29.18
C
ATOM
711
O
ASP
A
173
−10.512
21.341
25.994
1.00
28.08
O
ATOM
712
N
VAL
A
174
−11.483
23.071
27.081
1.00
27.66
N
ATOM
713
CA
VAL
A
174
−11.768
23.785
25.829
1.00
27.50
C
ATOM
714
CB
VAL
A
174
−12.677
25.024
26.047
1.00
28.13
C
ATOM
715
CG1
VAL
A
174
−12.760
25.860
24.766
1.00
27.42
C
ATOM
716
CG2
VAL
A
174
−14.062
24.576
26.464
1.00
26.02
C
ATOM
717
C
VAL
A
174
−10.459
24.167
25.150
1.00
28.12
C
ATOM
718
O
VAL
A
174
−10.288
23.952
23.912
1.00
26.80
O
ATOM
719
N
LYS
A
175
−9.517
24.720
25.913
1.00
27.32
N
ATOM
720
CA
LYS
A
175
−8.229
25.090
25.333
1.00
29.37
C
ATOM
721
CB
LYS
A
175
−7.336
25.851
26.319
1.00
29.49
C
ATOM
722
CG
LYS
A
175
−7.873
27.277
26.719
1.00
31.65
C
ATOM
723
CD
LYS
A
175
−7.042
27.779
27.947
1.00
34.24
C
ATOM
724
CE
LYS
A
175
−6.548
29.216
27.757
1.00
43.77
C
ATOM
725
NZ
LYS
A
175
−5.086
29.241
28.061
1.00
49.63
N
ATOM
726
C
LYS
A
175
−7.475
23.894
24.764
1.00
29.15
C
ATOM
727
O
LYS
A
175
−6.905
23.989
23.676
1.00
29.98
O
ATOM
728
N
ASN
A
176
−7.464
22.772
25.485
1.00
28.78
N
ATOM
729
CA
ASN
A
176
−6.806
21.577
24.971
1.00
29.56
C
ATOM
730
CB
ASN
A
176
−7.002
20.378
25.906
1.00
29.89
C
ATOM
731
CG
ASN
A
176
−6.190
20.483
27.181
1.00
37.18
C
ATOM
732
OD1
ASN
A
176
−6.501
19.795
28.175
1.00
42.17
O
ATOM
733
ND2
ASN
A
176
−5.141
21.338
27.178
1.00
41.19
N
ATOM
734
C
ASN
A
176
−7.387
21.203
23.614
1.00
27.60
C
ATOM
735
O
ASN
A
176
−6.648
20.894
22.683
1.00
27.59
O
ATOM
736
N
ALA
A
177
−8.705
21.202
23.527
1.00
25.47
N
ATOM
737
CA
ALA
A
177
−9.386
20.816
22.292
1.00
25.42
C
ATOM
738
CB
ALA
A
177
−10.899
20.715
22.505
1.00
23.91
C
ATOM
739
C
ALA
A
177
−9.070
21.744
21.148
1.00
24.79
C
ATOM
740
O
ALA
A
177
−8.944
21.266
20.001
1.00
25.02
O
ATOM
741
N
ILE
A
178
−9.013
23.060
21.440
1.00
23.30
N
ATOM
742
CA
ILE
A
178
−8.731
24.063
20.464
1.00
24.16
C
ATOM
743
CB
ILE
A
178
−8.883
25.496
21.039
1.00
23.64
C
ATOM
744
CG1
ILE
A
178
−10.344
25.862
21.218
1.00
23.43
C
ATOM
745
CD1
ILE
A
178
−10.566
27.275
21.940
1.00
24.62
C
ATOM
746
CG2
ILE
A
178
−8.167
26.518
20.104
1.00
24.53
C
ATOM
747
C
ILE
A
178
−7.307
23.869
19.924
1.00
25.28
C
ATOM
748
O
ILE
A
178
−7.076
23.950
18.708
1.00
23.52
O
ATOM
749
N
GLY
A
179
−6.361
23.568
20.821
1.00
25.82
N
ATOM
750
CA
GLY
A
179
−4.994
23.233
20.391
1.00
24.95
C
ATOM
751
C
GLY
A
179
−4.920
22.005
19.483
1.00
26.34
C
ATOM
752
O
GLY
A
179
−4.115
21.988
18.537
1.00
25.96
O
ATOM
753
N
VAL
A
180
−5.757
20.999
19.713
1.00
25.94
N
ATOM
754
CA
VAL
A
180
−5.748
19.794
18.840
1.00
27.50
C
ATOM
755
CB
VAL
A
180
−6.549
18.632
19.443
1.00
28.63
C
ATOM
756
CG1
VAL
A
180
−6.696
17.436
18.427
1.00
30.08
C
ATOM
757
CG2
VAL
A
180
−5.898
18.139
20.725
1.00
29.50
C
ATOM
758
C
VAL
A
180
−6.301
20.114
17.428
1.00
27.72
C
ATOM
759
O
VAL
A
180
−5.723
19.737
16.403
1.00
27.57
O
ATOM
760
N
LEU
A
181
−7.435
20.811
17.415
1.00
26.46
N
ATOM
761
CA
LEU
A
181
−8.043
21.334
16.195
1.00
26.40
C
ATOM
762
CB
LEU
A
181
−9.400
22.036
16.521
1.00
25.50
C
ATOM
763
CG
LEU
A
181
−10.103
22.583
15.258
1.00
25.35
C
ATOM
764
CD1
LEU
A
181
−10.370
21.411
14.239
1.00
23.23
C
ATOM
765
CD2
LEU
A
181
−11.377
23.348
15.605
1.00
25.48
C
ATOM
766
C
LEU
A
181
−7.092
22.262
15.412
1.00
25.60
C
ATOM
767
O
LEU
A
181
−6.849
22.045
14.207
1.00
23.63
O
ATOM
768
N
ILE
A
182
−6.577
23.300
16.058
1.00
24.97
N
ATOM
769
CA
ILE
A
182
−5.652
24.214
15.375
1.00
26.01
C
ATOM
770
CB
ILE
A
182
−5.196
25.420
16.291
1.00
26.44
C
ATOM
771
CG1
ILE
A
182
−6.341
26.404
16.468
1.00
26.81
C
ATOM
772
CD1
ILE
A
182
−6.078
27.572
17.483
1.00
25.50
C
ATOM
773
CG2
ILE
A
182
−4.006
26.171
15.657
1.00
26.76
C
ATOM
774
C
ILE
A
182
−4.401
23.498
14.849
1.00
27.06
C
ATOM
775
O
ILE
A
182
−3.903
23.798
13.737
1.00
27.99
O
ATOM
776
N
GLY
A
183
−3.903
22.544
15.625
1.00
26.95
N
ATOM
777
CA
GLY
A
183
−2.733
21.763
15.236
1.00
27.09
C
ATOM
778
C
GLY
A
183
−2.939
20.942
13.966
1.00
27.16
C
ATOM
779
O
GLY
A
183
−2.035
20.852
13.118
1.00
25.04
O
ATOM
780
N
GLY
A
184
−4.143
20.391
13.798
1.00
26.79
N
ATOM
781
CA
GLY
A
184
−4.454
19.527
12.642
1.00
26.69
C
ATOM
782
C
GLY
A
184
−4.633
20.410
11.450
1.00
26.33
C
ATOM
783
O
GLY
A
184
−4.127
20.120
10.380
1.00
26.17
O
ATOM
784
N
LEU
A
185
−5.313
21.534
11.638
1.00
26.30
N
ATOM
785
CA
LEU
A
185
−5.499
22.492
10.565
1.00
24.55
C
ATOM
786
CB
LEU
A
185
−6.415
23.616
11.001
1.00
23.84
C
ATOM
787
CG
LEU
A
185
−7.888
23.220
11.293
1.00
23.68
C
ATOM
788
CD1
LEU
A
185
−8.599
24.422
12.020
1.00
23.04
C
ATOM
789
CD2
LEU
A
185
−8.559
22.845
9.959
1.00
21.51
C
ATOM
790
C
LEU
A
185
−4.175
23.072
10.089
1.00
26.07
C
ATOM
791
O
LEU
A
185
−3.967
23.195
8.863
1.00
24.84
O
ATOM
792
N
GLU
A
186
−3.320
23.489
11.021
1.00
24.68
N
ATOM
793
CA
GLU
A
186
−1.974
24.029
10.643
1.00
26.89
C
ATOM
794
CB
GLU
A
186
−1.271
24.702
11.828
1.00
26.28
C
ATOM
795
CG
GLU
A
186
−1.956
25.957
12.224
1.00
29.68
C
ATOM
796
CD
GLU
A
186
−1.329
26.627
13.460
1.00
30.75
C
ATOM
797
OE1
GLU
A
186
−0.559
25.977
14.192
1.00
36.73
O
ATOM
798
OE2
GLU
A
186
−1.625
27.804
13.670
1.00
33.71
O
ATOM
799
C
GLU
A
186
−1.046
23.007
10.020
1.00
27.78
C
ATOM
800
O
GLU
A
186
−0.236
23.366
9.102
1.00
28.87
O
ATOM
801
N
TRP
A
187
−1.120
21.762
10.495
1.00
29.22
N
ATOM
802
CA
TRP
A
187
−0.402
20.622
9.874
1.00
30.02
C
ATOM
803
CB
TRP
A
187
−0.669
19.278
10.586
1.00
31.40
C
ATOM
804
CG
TRP
A
187
−0.339
17.955
9.756
1.00
33.36
C
ATOM
805
CD1
TRP
A
187
−1.180
17.266
8.885
1.00
36.81
C
ATOM
806
NE1
TRP
A
187
−0.563
16.136
8.391
1.00
37.42
N
ATOM
807
CE2
TRP
A
187
0.699
16.083
8.919
1.00
38.06
C
ATOM
808
CD2
TRP
A
187
0.869
17.200
9.788
1.00
35.93
C
ATOM
809
CE3
TRP
A
187
2.079
17.363
10.464
1.00
35.96
C
ATOM
810
CZ3
TRP
A
187
3.041
16.448
10.268
1.00
38.27
C
ATOM
811
CH2
TRP
A
187
2.857
15.350
9.386
1.00
37.53
C
ATOM
812
CZ2
TRP
A
187
1.676
15.149
8.721
1.00
36.20
C
ATOM
813
C
TRP
A
187
−0.753
20.517
8.387
1.00
29.83
C
ATOM
814
O
TRP
A
187
0.135
20.246
7.539
1.00
27.61
O
ATOM
815
N
ASN
A
188
−2.037
20.751
8.078
1.00
28.16
N
ATOM
816
CA
ASN
A
188
−2.521
20.755
6.679
1.00
28.81
C
ATOM
817
CB
ASN
A
188
−4.018
20.335
6.628
1.00
27.28
C
ATOM
818
CG
ASN
A
188
−4.189
18.844
6.447
1.00
27.85
C
ATOM
819
OD1
ASN
A
188
−3.221
18.120
6.229
1.00
30.13
O
ATOM
820
ND2
ASN
A
188
−5.416
18.367
6.562
1.00
25.16
N
ATOM
821
C
ASN
A
188
−2.317
22.083
5.939
1.00
28.69
C
ATOM
822
O
ASN
A
188
−2.976
22.351
4.912
1.00
28.16
O
ATOM
823
N
ASP
A
189
−1.417
22.916
6.453
1.00
28.38
N
ATOM
824
CA
ASP
A
189
−1.064
24.186
5.841
1.00
29.63
C
ATOM
825
CB
ASP
A
189
−0.361
23.927
4.472
1.00
30.44
C
ATOM
826
CG
ASP
A
189
0.978
23.255
4.654
1.00
34.49
C
ATOM
827
OD1
ASP
A
189
1.747
23.745
5.545
1.00
36.20
O
ATOM
828
OD2
ASP
A
189
1.210
22.192
4.008
1.00
37.75
O
ATOM
829
C
ASP
A
189
−2.195
25.185
5.706
1.00
29.23
C
ATOM
830
O
ASP
A
189
−2.196
26.026
4.788
1.00
29.61
O
ATOM
831
N
ASN
A
190
−3.161
25.105
6.622
1.00
28.19
N
ATOM
832
CA
ASN
A
190
−4.158
26.126
6.724
1.00
27.21
C
ATOM
833
CB
ASN
A
190
−5.511
25.547
7.254
1.00
25.60
C
ATOM
834
CG
ASN
A
190
−6.073
24.485
6.339
1.00
24.16
C
ATOM
835
OD1
ASN
A
190
−6.548
24.789
5.248
1.00
25.54
O
ATOM
836
ND2
ASN
A
190
−5.995
23.233
6.751
1.00
22.44
N
ATOM
837
C
ASN
A
190
−3.634
27.215
7.618
1.00
27.62
C
ATOM
838
O
ASN
A
190
−2.931
26.923
8.583
1.00
28.53
O
ATOM
839
N
THR
A
191
−4.001
28.457
7.307
1.00
28.23
N
ATOM
840
CA
THR
A
191
−3.761
29.597
8.193
1.00
28.87
C
ATOM
841
CB
THR
A
191
−3.396
30.833
7.361
1.00
29.15
C
ATOM
842
OG1
THR
A
191
−2.188
30.538
6.652
1.00
31.36
O
ATOM
843
CG2
THR
A
191
−3.171
32.049
8.277
1.00
31.30
C
ATOM
844
C
THR
A
191
−5.006
29.843
9.099
1.00
27.84
C
ATOM
845
O
THR
A
191
−6.096
30.157
8.622
1.00
27.93
O
ATOM
846
N
VAL
A
192
−4.813
29.688
10.406
1.00
28.14
N
ATOM
847
CA
VAL
A
192
−5.905
29.719
11.400
1.00
27.77
C
ATOM
848
CB
VAL
A
192
−5.808
28.512
12.350
1.00
26.87
C
ATOM
849
CG1
VAL
A
192
−7.022
28.475
13.300
1.00
27.00
C
ATOM
850
CG2
VAL
A
192
−5.690
27.162
11.532
1.00
26.44
C
ATOM
851
C
VAL
A
192
−5.905
31.048
12.235
1.00
29.05
C
ATOM
852
O
VAL
A
192
−4.876
31.468
12.806
1.00
29.85
O
ATOM
853
N
ARG
A
193
−7.048
31.703
12.284
1.00
27.96
N
ATOM
854
CA
ARG
A
193
−7.233
32.827
13.169
1.00
29.69
C
ATOM
855
CB
ARG
A
193
−7.559
34.100
12.385
1.00
29.62
C
ATOM
856
CG
ARG
A
193
−6.444
34.579
11.482
1.00
33.74
C
ATOM
857
CD
ARG
A
193
−6.956
35.638
10.516
1.00
41.01
C
ATOM
858
NE
ARG
A
193
−5.825
36.233
9.767
1.00
50.62
N
ATOM
859
CZ
ARG
A
193
−5.238
35.718
8.668
1.00
53.47
C
ATOM
860
NH1
ARG
A
193
−5.633
34.559
8.129
1.00
54.25
N
ATOM
861
NH2
ARG
A
193
−4.234
36.372
8.095
1.00
55.59
N
ATOM
862
C
ARG
A
193
−8.438
32.451
14.049
1.00
29.25
C
ATOM
863
O
ARG
A
193
−9.275
31.619
13.660
1.00
26.12
O
ATOM
864
N
VAL
A
194
−8.523
33.085
15.219
1.00
30.07
N
ATOM
865
CA
VAL
A
194
−9.676
32.896
16.113
1.00
29.06
C
ATOM
866
CB
VAL
A
194
−9.270
32.162
17.470
1.00
31.71
C
ATOM
867
CG1
VAL
A
194
−8.265
31.013
17.189
1.00
29.70
C
ATOM
868
CG2
VAL
A
194
−8.693
33.093
18.509
1.00
29.72
C
ATOM
869
C
VAL
A
194
−10.418
34.195
16.316
1.00
28.87
C
ATOM
870
O
VAL
A
194
−9.806
35.286
16.243
1.00
27.66
O
ATOM
871
N
SER
A
195
−11.728
34.104
16.556
1.00
27.12
N
ATOM
872
CA
SER
A
195
−12.581
35.299
16.612
1.00
26.89
C
ATOM
873
CB
SER
A
195
−14.036
34.898
16.873
1.00
27.31
C
ATOM
874
OG
SER
A
195
−14.129
34.257
18.174
1.00
25.66
O
ATOM
875
C
SER
A
195
−12.115
36.220
17.747
1.00
25.66
C
ATOM
876
O
SER
A
195
−11.402
35.785
18.657
1.00
24.47
O
ATOM
877
N
LYS
A
196
−12.566
37.463
17.725
1.00
26.32
N
ATOM
878
CA
LYS
A
196
−12.108
38.399
18.767
1.00
27.97
C
ATOM
879
CB
LYS
A
196
−12.581
39.815
18.418
1.00
27.76
C
ATOM
880
CG
LYS
A
196
−11.677
40.430
17.375
1.00
34.20
C
ATOM
881
CD
LYS
A
196
−12.432
41.396
16.488
1.00
42.92
C
ATOM
882
CE
LYS
A
196
−11.522
41.909
15.355
1.00
47.63
C
ATOM
883
NZ
LYS
A
196
−10.391
42.734
15.894
1.00
49.98
N
ATOM
884
C
LYS
A
196
−12.635
37.965
20.148
1.00
27.45
C
ATOM
885
O
LYS
A
196
−11.968
38.176
21.156
1.00
27.97
O
ATOM
886
N
THR
A
197
−13.844
37.390
20.179
1.00
26.73
N
ATOM
887
CA
THR
A
197
−14.400
36.946
21.454
1.00
27.39
C
ATOM
888
CB
THR
A
197
−15.880
36.620
21.372
1.00
27.32
C
ATOM
889
OG1
THR
A
197
−16.083
35.558
20.440
1.00
28.59
O
ATOM
890
CG2
THR
A
197
−16.681
37.817
20.891
1.00
27.51
C
ATOM
891
C
THR
A
197
−13.644
35.749
21.981
1.00
27.16
C
ATOM
892
O
THR
A
197
−13.384
35.655
23.195
1.00
26.76
O
ATOM
893
N
LEU
A
198
−13.258
34.825
21.092
1.00
26.56
N
ATOM
894
CA
LEU
A
198
−12.361
33.734
21.518
1.00
26.73
C
ATOM
895
CB
LEU
A
198
−12.098
32.702
20.382
1.00
27.47
C
ATOM
896
CG
LEU
A
198
−13.233
31.710
20.187
1.00
26.53
C
ATOM
897
CD1
LEU
A
198
−12.970
30.817
18.963
1.00
29.55
C
ATOM
898
CD2
LEU
A
198
−13.370
30.815
21.453
1.00
24.14
C
ATOM
899
C
LEU
A
198
−11.034
34.250
22.063
1.00
26.63
C
ATOM
900
O
LEU
A
198
−10.534
33.728
23.060
1.00
26.63
O
ATOM
901
N
GLN
A
199
−10.459
35.262
21.421
1.00
27.02
N
ATOM
902
CA
GLN
A
199
−9.203
35.819
21.900
1.00
29.00
C
ATOM
903
CB
GLN
A
199
−8.696
36.933
20.987
1.00
29.92
C
ATOM
904
CG
GLN
A
199
−8.078
36.484
19.696
1.00
35.17
C
ATOM
905
CD
GLN
A
199
−7.910
37.677
18.755
1.00
42.65
C
ATOM
906
OE1
GLN
A
199
−7.473
38.789
19.167
1.00
43.78
O
ATOM
907
NE2
GLN
A
199
−8.321
37.487
17.512
1.00
41.52
N
ATOM
908
C
GLN
A
199
−9.405
36.416
23.278
1.00
28.53
C
ATOM
909
O
GLN
A
199
−8.591
36.225
24.191
1.00
27.18
O
ATOM
910
N
ARG
A
200
−10.498
37.155
23.408
1.00
28.92
N
ATOM
911
CA
ARG
A
200
−10.796
37.871
24.666
1.00
27.60
C
ATOM
912
CB
ARG
A
200
−12.077
38.707
24.481
1.00
28.09
C
ATOM
913
CG
ARG
A
200
−12.551
39.551
25.731
1.00
27.90
C
ATOM
914
CD
ARG
A
200
−13.718
40.446
25.377
1.00
26.48
C
ATOM
915
NE
ARG
A
200
−13.279
41.396
24.356
1.00
30.07
N
ATOM
916
CZ
ARG
A
200
−13.768
41.476
23.104
1.00
28.44
C
ATOM
917
NH1
ARG
A
200
−14.793
40.738
22.716
1.00
26.58
N
ATOM
918
NH2
ARG
A
200
−13.232
42.345
22.237
1.00
28.69
N
ATOM
919
C
ARG
A
200
−10.968
36.934
25.859
1.00
28.34
C
ATOM
920
O
ARG
A
200
−10.491
37.238
26.955
1.00
28.25
O
ATOM
921
N
PHE
A
201
−11.706
35.848
25.660
1.00
28.84
N
ATOM
922
CA
PHE
A
201
−12.244
35.004
26.738
1.00
28.86
C
ATOM
923
CB
PHE
A
201
−13.772
34.828
26.559
1.00
28.35
C
ATOM
924
CG
PHE
A
201
−14.568
36.097
26.766
1.00
25.52
C
ATOM
925
CD1
PHE
A
201
−14.554
36.770
27.997
1.00
27.82
C
ATOM
926
CE1
PHE
A
201
−15.273
37.974
28.166
1.00
27.90
C
ATOM
927
CZ
PHE
A
201
−16.034
38.498
27.120
1.00
28.95
C
ATOM
928
CE2
PHE
A
201
−16.063
37.831
25.899
1.00
27.66
C
ATOM
929
CD2
PHE
A
201
−15.319
36.623
25.735
1.00
27.72
C
ATOM
930
C
PHE
A
201
−11.563
33.627
26.884
1.00
30.86
C
ATOM
931
O
PHE
A
201
−11.721
32.964
27.915
1.00
30.47
O
ATOM
932
N
ALA
A
202
−10.780
33.200
25.895
1.00
31.85
N
ATOM
933
CA
ALA
A
202
−10.326
31.801
25.894
1.00
34.65
C
ATOM
934
CB
ALA
A
202
−11.347
30.904
25.154
1.00
32.12
C
ATOM
935
C
ALA
A
202
−8.924
31.544
25.367
1.00
37.14
C
ATOM
936
O
ALA
A
202
−8.222
30.715
25.921
1.00
38.77
O
ATOM
937
N
TRP
A
203
−8.523
32.260
24.307
1.00
38.77
N
ATOM
938
CA
TRP
A
203
−7.316
31.934
23.527
1.00
40.33
C
ATOM
939
CB
TRP
A
203
−7.720
31.335
22.174
1.00
38.58
C
ATOM
940
CG
TRP
A
203
−6.610
30.594
21.453
1.00
38.71
C
ATOM
941
CD1
TRP
A
203
−5.864
31.038
20.370
1.00
37.42
C
ATOM
942
NE1
TRP
A
203
−4.978
30.057
19.965
1.00
37.40
N
ATOM
943
CE2
TRP
A
203
−5.106
28.975
20.808
1.00
36.87
C
ATOM
944
CD2
TRP
A
203
−6.134
29.284
21.754
1.00
36.44
C
ATOM
945
CE3
TRP
A
203
−6.459
28.335
22.740
1.00
38.19
C
ATOM
946
CZ3
TRP
A
203
−5.762
27.090
22.750
1.00
37.22
C
ATOM
947
CH2
TRP
A
203
−4.749
26.813
21.786
1.00
36.78
C
ATOM
948
CZ2
TRP
A
203
−4.406
27.742
20.821
1.00
36.69
C
ATOM
949
C
TRP
A
203
−6.525
33.207
23.251
1.00
42.00
C
ATOM
950
O
TRP
A
203
−6.552
33.692
22.103
1.00
44.02
O
ATOM
951
OXT
TRP
A
203
−5.876
33.797
24.117
1.00
42.42
O
ATOM
952
N
PRO
B
85
7.442
25.386
−43.697
1.00
62.33
N
ATOM
953
CA
PRO
B
85
8.153
26.040
−42.594
1.00
61.88
C
ATOM
954
CB
PRO
B
85
7.082
26.935
−41.948
1.00
62.07
C
ATOM
955
CG
PRO
B
85
6.069
27.170
−43.026
1.00
62.66
C
ATOM
956
CD
PRO
B
85
6.075
25.911
−43.875
1.00
62.82
C
ATOM
957
C
PRO
B
85
8.678
25.031
−41.572
1.00
60.95
C
ATOM
958
O
PRO
B
85
7.988
24.045
−41.269
1.00
61.39
O
ATOM
959
N
ALA
B
86
9.893
25.269
−41.064
1.00
59.55
N
ATOM
960
CA
ALA
B
86
10.476
24.427
−40.026
1.00
58.13
C
ATOM
961
CB
ALA
B
86
11.886
24.854
−39.737
1.00
58.01
C
ATOM
962
C
ALA
B
86
9.618
24.453
−38.750
1.00
57.61
C
ATOM
963
O
ALA
B
86
8.875
25.413
−38.517
1.00
57.45
O
ATOM
964
N
SER
B
87
9.699
23.382
−37.955
1.00
56.80
N
ATOM
965
CA
SER
B
87
9.094
23.341
−36.621
1.00
55.97
C
ATOM
966
CB
SER
B
87
9.578
22.115
−35.841
1.00
56.09
C
ATOM
967
OG
SER
B
87
9.096
20.914
−36.416
1.00
59.57
O
ATOM
968
C
SER
B
87
9.504
24.568
−35.832
1.00
54.53
C
ATOM
969
O
SER
B
87
10.638
25.044
−35.952
1.00
53.79
O
ATOM
970
N
ARG
B
88
8.587
25.081
−35.022
1.00
53.11
N
ATOM
971
CA
ARG
B
88
8.994
26.013
−33.978
1.00
51.52
C
ATOM
972
CB
ARG
B
88
8.504
27.432
−34.252
1.00
52.04
C
ATOM
973
CG
ARG
B
88
7.041
27.550
−34.529
1.00
54.33
C
ATOM
974
CD
ARG
B
88
6.728
28.924
−35.062
1.00
57.93
C
ATOM
975
NE
ARG
B
88
5.363
29.328
−34.759
1.00
60.15
N
ATOM
976
CZ
ARG
B
88
5.012
30.052
−33.699
1.00
63.10
C
ATOM
977
NH1
ARG
B
88
5.932
30.458
−32.815
1.00
62.43
N
ATOM
978
NH2
ARG
B
88
3.730
30.373
−33.519
1.00
62.59
N
ATOM
979
C
ARG
B
88
8.537
25.490
−32.617
1.00
49.39
C
ATOM
980
O
ARG
B
88
7.619
24.684
−32.550
1.00
47.87
O
ATOM
981
N
TYR
B
89
9.217
25.943
−31.567
1.00
47.24
N
ATOM
982
CA
TYR
B
89
8.982
25.477
−30.204
1.00
45.49
C
ATOM
983
CB
TYR
B
89
10.298
25.132
−29.498
1.00
46.96
C
ATOM
984
CG
TYR
B
89
10.938
23.840
−29.949
1.00
49.23
C
ATOM
985
CD1
TYR
B
89
12.003
23.859
−30.844
1.00
51.93
C
ATOM
986
CE1
TYR
B
89
12.614
22.678
−31.274
1.00
53.21
C
ATOM
987
CZ
TYR
B
89
12.159
21.453
−30.800
1.00
52.97
C
ATOM
988
OH
TYR
B
89
12.793
20.295
−31.238
1.00
52.46
O
ATOM
989
CE2
TYR
B
89
11.089
21.403
−29.901
1.00
51.87
C
ATOM
990
CD2
TYR
B
89
10.485
22.596
−29.482
1.00
50.16
C
ATOM
991
C
TYR
B
89
8.251
26.525
−29.391
1.00
43.03
C
ATOM
992
O
TYR
B
89
8.599
27.718
−29.405
1.00
42.37
O
ATOM
993
N
ILE
B
90
7.230
26.066
−28.685
1.00
39.81
N
ATOM
994
CA
ILE
B
90
6.552
26.883
−27.712
1.00
37.00
C
ATOM
995
CB
ILE
B
90
5.018
26.620
−27.746
1.00
37.76
C
ATOM
996
CG1
ILE
B
90
4.414
26.837
−29.163
1.00
37.36
C
ATOM
997
CD1
ILE
B
90
4.795
28.145
−29.862
1.00
39.19
C
ATOM
998
CG2
ILE
B
90
4.317
27.434
−26.660
1.00
34.76
C
ATOM
999
C
ILE
B
90
7.120
26.456
−26.366
1.00
36.01
C
ATOM
1000
O
ILE
B
90
7.290
25.244
−26.111
1.00
34.34
O
ATOM
1001
N
THR
B
91
7.455
27.422
−25.516
1.00
35.22
N
ATOM
1002
CA
THR
B
91
8.016
27.093
−24.204
1.00
35.55
C
ATOM
1003
CB
THR
B
91
9.552
27.381
−24.113
1.00
36.05
C
ATOM
1004
OG1
THR
B
91
9.811
28.768
−24.427
1.00
37.96
O
ATOM
1005
CG2
THR
B
91
10.350
26.466
−25.020
1.00
37.46
C
ATOM
1006
C
THR
B
91
7.286
27.902
−23.156
1.00
35.72
C
ATOM
1007
O
THR
B
91
7.699
29.018
−22.827
1.00
35.37
O
ATOM
1008
N
ASP
B
92
6.161
27.373
−22.666
1.00
35.05
N
ATOM
1009
CA
ASP
B
92
5.366
28.077
−21.650
1.00
33.77
C
ATOM
1010
CB
ASP
B
92
4.034
27.364
−21.361
1.00
33.89
C
ATOM
1011
CG
ASP
B
92
2.992
27.502
−22.482
1.00
34.60
C
ATOM
1012
OD1
ASP
B
92
3.154
28.326
−23.431
1.00
35.61
O
ATOM
1013
OD2
ASP
B
92
1.975
26.774
−22.383
1.00
33.13
O
ATOM
1014
C
ASP
B
92
6.146
28.082
−20.349
1.00
33.53
C
ATOM
1015
O
ASP
B
92
6.056
29.033
−19.578
1.00
33.40
O
ATOM
1016
N
MET
B
93
6.878
27.009
−20.083
1.00
32.58
N
ATOM
1017
CA
MET
B
93
7.539
26.857
−18.794
1.00
32.30
C
ATOM
1018
CB
MET
B
93
7.607
25.369
−18.402
1.00
32.52
C
ATOM
1019
CG
MET
B
93
6.322
24.773
−17.914
1.00
29.43
C
ATOM
1020
SD
MET
B
93
6.429
23.054
−17.472
1.00
28.89
S
ATOM
1021
CE
MET
B
93
5.883
22.183
−18.940
1.00
26.92
C
ATOM
1022
C
MET
B
93
8.983
27.427
−18.831
1.00
34.01
C
ATOM
1023
O
MET
B
93
9.657
27.323
−19.864
1.00
32.66
O
ATOM
1024
N
THR
B
94
9.457
27.980
−17.704
1.00
34.20
N
ATOM
1025
CA
THR
B
94
10.880
28.311
−17.544
1.00
35.22
C
ATOM
1026
CB
THR
B
94
11.120
29.178
−16.266
1.00
36.09
C
ATOM
1027
OG1
THR
B
94
10.674
28.440
−15.134
1.00
36.40
O
ATOM
1028
CG2
THR
B
94
10.354
30.513
−16.315
1.00
35.20
C
ATOM
1029
C
THR
B
94
11.727
27.047
−17.428
1.00
34.67
C
ATOM
1030
O
THR
B
94
11.199
25.961
−17.197
1.00
33.47
O
ATOM
1031
N
ILE
B
95
13.051
27.175
−17.583
1.00
35.62
N
ATOM
1032
CA
ILE
B
95
13.960
26.054
−17.369
1.00
36.37
C
ATOM
1033
CB
ILE
B
95
15.499
26.465
−17.487
1.00
36.16
C
ATOM
1034
CG1
ILE
B
95
15.815
26.979
−18.895
1.00
39.79
C
ATOM
1035
CD1
ILE
B
95
17.240
27.642
−19.070
1.00
39.32
C
ATOM
1036
CG2
ILE
B
95
16.343
25.262
−17.243
1.00
36.87
C
ATOM
1037
C
ILE
B
95
13.739
25.427
−15.998
1.00
35.94
C
ATOM
1038
O
ILE
B
95
13.831
24.194
−15.836
1.00
36.49
O
ATOM
1039
N
GLU
B
96
13.509
26.257
−14.993
1.00
36.30
N
ATOM
1040
CA
GLU
B
96
13.309
25.726
−13.628
1.00
37.91
C
ATOM
1041
CB
GLU
B
96
13.372
26.878
−12.596
1.00
38.48
C
ATOM
1042
CG
GLU
B
96
13.421
26.440
−11.134
1.00
41.71
C
ATOM
1043
CD
GLU
B
96
12.042
26.159
−10.555
1.00
45.38
C
ATOM
1044
OE1
GLU
B
96
11.042
26.752
−11.042
1.00
47.09
O
ATOM
1045
OE2
GLU
B
96
11.967
25.354
−9.600
1.00
46.98
O
ATOM
1046
C
GLU
B
96
11.995
24.913
−13.517
1.00
36.88
C
ATOM
1047
O
GLU
B
96
11.977
23.805
−12.997
1.00
36.45
O
ATOM
1048
N
GLU
B
97
10.909
25.477
−14.028
1.00
36.87
N
ATOM
1049
CA
GLU
B
97
9.602
24.789
−14.010
1.00
36.88
C
ATOM
1050
CB
GLU
B
97
8.552
25.667
−14.663
1.00
36.11
C
ATOM
1051
CG
GLU
B
97
8.177
26.883
−13.781
1.00
38.37
C
ATOM
1052
CD
GLU
B
97
7.264
27.884
−14.452
1.00
38.94
C
ATOM
1053
OE1
GLU
B
97
7.424
28.160
−15.681
1.00
38.42
O
ATOM
1054
OE2
GLU
B
97
6.399
28.435
−13.725
1.00
41.47
O
ATOM
1055
C
GLU
B
97
9.662
23.414
−14.664
1.00
36.23
C
ATOM
1056
O
GLU
B
97
9.071
22.443
−14.171
1.00
36.44
O
ATOM
1057
N
LEU
B
98
10.409
23.313
−15.760
1.00
35.44
N
ATOM
1058
CA
LEU
B
98
10.447
22.090
−16.543
1.00
36.09
C
ATOM
1059
CB
LEU
B
98
10.992
22.400
−17.941
1.00
37.24
C
ATOM
1060
CG
LEU
B
98
10.961
21.395
−19.103
1.00
41.62
C
ATOM
1061
CD1
LEU
B
98
9.587
21.306
−19.833
1.00
41.32
C
ATOM
1062
CD2
LEU
B
98
12.004
21.864
−20.095
1.00
45.35
C
ATOM
1063
C
LEU
B
98
11.290
21.025
−15.870
1.00
36.56
C
ATOM
1064
O
LEU
B
98
11.003
19.822
−15.985
1.00
35.75
O
ATOM
1065
N
SER
B
99
12.322
21.470
−15.156
1.00
37.20
N
ATOM
1066
CA
SER
B
99
13.294
20.563
−14.547
1.00
38.65
C
ATOM
1067
CB
SER
B
99
14.666
21.226
−14.525
1.00
39.66
C
ATOM
1068
OG
SER
B
99
14.626
22.393
−13.710
1.00
45.01
O
ATOM
1069
C
SER
B
99
12.934
20.161
−13.136
1.00
37.67
C
ATOM
1070
O
SER
B
99
13.387
19.139
−12.682
1.00
37.38
O
ATOM
1071
N
ARG
B
100
12.101
20.962
−12.457
1.00
38.83
N
ATOM
1072
CA
ARG
B
100
11.673
20.677
−11.071
1.00
38.07
C
ATOM
1073
CB
ARG
B
100
10.594
21.675
−10.658
1.00
39.03
C
ATOM
1074
CG
ARG
B
100
10.454
21.834
−9.166
1.00
40.88
C
ATOM
1075
CD
ARG
B
100
9.310
22.774
−8.836
1.00
40.98
C
ATOM
1076
NE
ARG
B
100
9.423
24.092
−9.464
1.00
39.64
N
ATOM
1077
CZ
ARG
B
100
8.392
24.898
−9.644
1.00
40.56
C
ATOM
1078
NH1
ARG
B
100
7.189
24.515
−9.231
1.00
44.30
N
ATOM
1079
NH2
ARG
B
100
8.550
26.090
−10.198
1.00
42.36
N
ATOM
1080
C
ARG
B
100
11.121
19.261
−10.945
1.00
37.43
C
ATOM
1081
O
ARG
B
100
10.438
18.783
−11.846
1.00
36.57
O
ATOM
1082
N
ASP
B
101
11.453
18.564
−9.860
1.00
35.80
N
ATOM
1083
CA
ASP
B
101
10.742
17.342
−9.523
1.00
35.10
C
ATOM
1084
CB
ASP
B
101
11.651
16.271
−8.899
1.00
35.75
C
ATOM
1085
CG
ASP
B
101
12.806
15.834
−9.812
1.00
37.07
C
ATOM
1086
OD1
ASP
B
101
12.570
15.518
−11.012
1.00
35.64
O
ATOM
1087
OD2
ASP
B
101
13.952
15.733
−9.275
1.00
38.34
O
ATOM
1088
C
ASP
B
101
9.690
17.753
−8.500
1.00
34.47
C
ATOM
1089
O
ASP
B
101
9.912
18.665
−7.681
1.00
35.01
O
ATOM
1090
N
TRP
B
102
8.540
17.093
−8.525
1.00
33.32
N
ATOM
1091
CA
TRP
B
102
7.468
17.502
−7.641
1.00
31.72
C
ATOM
1092
CB
TRP
B
102
6.491
18.411
−8.419
1.00
32.70
C
ATOM
1093
CG
TRP
B
102
5.866
17.687
−9.554
1.00
30.91
C
ATOM
1094
CD1
TRP
B
102
6.433
17.389
−10.754
1.00
31.44
C
ATOM
1095
NE1
TRP
B
102
5.544
16.652
−11.540
1.00
33.38
N
ATOM
1096
CE2
TRP
B
102
4.386
16.454
−10.833
1.00
34.03
C
ATOM
1097
CD2
TRP
B
102
4.562
17.079
−9.552
1.00
34.03
C
ATOM
1098
CE3
TRP
B
102
3.512
17.033
−8.620
1.00
33.01
C
ATOM
1099
CZ3
TRP
B
102
2.309
16.373
−8.993
1.00
30.04
C
ATOM
1100
CH2
TRP
B
102
2.188
15.734
−10.255
1.00
31.03
C
ATOM
1101
CZ2
TRP
B
102
3.206
15.764
−11.184
1.00
31.94
C
ATOM
1102
C
TRP
B
102
6.829
16.320
−6.880
1.00
31.64
C
ATOM
1103
O
TRP
B
102
7.038
15.140
−7.209
1.00
31.20
O
ATOM
1104
N
PHE
B
103
6.114
16.653
−5.800
1.00
30.85
N
ATOM
1105
CA
PHE
B
103
5.628
15.684
−4.827
1.00
29.60
C
ATOM
1106
CB
PHE
B
103
6.029
16.180
−3.425
1.00
30.18
C
ATOM
1107
CG
PHE
B
103
5.321
15.507
−2.268
1.00
31.54
C
ATOM
1108
CD1
PHE
B
103
5.742
14.284
−1.798
1.00
31.56
C
ATOM
1109
CE1
PHE
B
103
5.122
13.681
−0.692
1.00
30.41
C
ATOM
1110
CZ
PHE
B
103
4.055
14.329
−0.046
1.00
31.78
C
ATOM
1111
CE2
PHE
B
103
3.635
15.599
−0.483
1.00
30.83
C
ATOM
1112
CD2
PHE
B
103
4.273
16.174
−1.597
1.00
33.14
C
ATOM
1113
C
PHE
B
103
4.118
15.612
−4.935
1.00
27.88
C
ATOM
1114
O
PHE
B
103
3.473
16.646
−5.063
1.00
28.45
O
ATOM
1115
N
MET
B
104
3.598
14.391
−4.875
1.00
27.19
N
ATOM
1116
CA
MET
B
104
2.163
14.120
−4.772
1.00
27.44
C
ATOM
1117
CB
MET
B
104
1.715
13.163
−5.899
1.00
26.04
C
ATOM
1118
CG
MET
B
104
1.798
13.758
−7.355
1.00
28.37
C
ATOM
1119
SD
MET
B
104
1.632
12.389
−8.528
1.00
26.62
S
ATOM
1120
CE
MET
B
104
3.295
11.830
−8.571
1.00
26.34
C
ATOM
1121
C
MET
B
104
1.913
13.456
−3.389
1.00
27.60
C
ATOM
1122
O
MET
B
104
2.502
12.434
−3.068
1.00
26.49
O
ATOM
1123
N
LEU
B
105
1.056
14.072
−2.583
1.00
26.42
N
ATOM
1124
CA
LEU
B
105
0.616
13.447
−1.317
1.00
26.58
C
ATOM
1125
CB
LEU
B
105
−0.240
14.454
−0.508
1.00
25.53
C
ATOM
1126
CG
LEU
B
105
−0.660
14.024
0.917
1.00
28.52
C
ATOM
1127
CD1
LEU
B
105
0.620
13.782
1.774
1.00
26.80
C
ATOM
1128
CD2
LEU
B
105
−1.509
15.149
1.416
1.00
28.79
C
ATOM
1129
C
LEU
B
105
−0.185
12.189
−1.571
1.00
26.02
C
ATOM
1130
O
LEU
B
105
−0.030
11.227
−0.858
1.00
26.32
O
ATOM
1131
N
MET
B
106
−1.086
12.213
−2.572
1.00
26.57
N
ATOM
1132
CA
MET
B
106
−1.909
11.043
−2.919
1.00
25.33
C
ATOM
1133
CB
MET
B
106
−3.414
11.381
−2.722
1.00
24.16
C
ATOM
1134
CG
MET
B
106
−3.718
11.818
−1.267
1.00
27.74
C
ATOM
1135
SD
MET
B
106
−5.495
12.138
−1.007
1.00
25.66
S
ATOM
1136
CE
MET
B
106
−5.818
10.701
0.032
1.00
35.03
C
ATOM
1137
C
MET
B
106
−1.641
10.741
−4.397
1.00
26.10
C
ATOM
1138
O
MET
B
106
−2.439
11.106
−5.263
1.00
24.95
O
ATOM
1139
N
PRO
B
107
−0.515
10.079
−4.684
1.00
27.23
N
ATOM
1140
CA
PRO
B
107
−0.083
9.969
−6.107
1.00
26.85
C
ATOM
1141
CB
PRO
B
107
1.220
9.184
−6.024
1.00
26.93
C
ATOM
1142
CG
PRO
B
107
1.622
9.205
−4.482
1.00
26.97
C
ATOM
1143
CD
PRO
B
107
0.333
9.284
−3.763
1.00
26.75
C
ATOM
1144
C
PRO
B
107
−1.085
9.168
−6.958
1.00
26.73
C
ATOM
1145
O
PRO
B
107
−1.699
8.178
−6.490
1.00
26.39
O
ATOM
1146
N
LYS
B
108
−1.238
9.625
−8.202
1.00
27.58
N
ATOM
1147
CA
LYS
B
108
−2.047
8.964
−9.208
1.00
28.66
C
ATOM
1148
CB
LYS
B
108
−3.361
9.741
−9.422
1.00
28.49
C
ATOM
1149
CG
LYS
B
108
−4.375
9.513
−8.277
1.00
28.11
C
ATOM
1150
CD
LYS
B
108
−4.773
8.044
−8.260
1.00
30.78
C
ATOM
1151
CE
LYS
B
108
−5.300
7.575
−6.971
1.00
32.01
C
ATOM
1152
NZ
LYS
B
108
−4.282
7.664
−5.906
1.00
33.62
N
ATOM
1153
C
LYS
B
108
−1.212
9.009
−10.485
1.00
28.71
C
ATOM
1154
O
LYS
B
108
−0.620
10.034
−10.802
1.00
28.16
O
ATOM
1155
N
GLN
B
109
−1.132
7.879
−11.171
1.00
30.52
N
ATOM
1156
CA
GLN
B
109
−0.373
7.809
−12.435
1.00
33.68
C
ATOM
1157
CB
GLN
B
109
1.078
7.372
−12.187
1.00
34.23
C
ATOM
1158
CG
GLN
B
109
1.943
7.302
−13.432
1.00
39.99
C
ATOM
1159
CD
GLN
B
109
3.272
6.642
−13.153
1.00
47.20
C
ATOM
1160
OE1
GLN
B
109
4.126
7.218
−12.489
1.00
52.68
O
ATOM
1161
NE2
GLN
B
109
3.448
5.416
−13.636
1.00
51.24
N
ATOM
1162
C
GLN
B
109
−1.066
6.845
−13.352
1.00
34.01
C
ATOM
1163
O
GLN
B
109
−1.408
5.722
−12.931
1.00
34.27
O
ATOM
1164
N
LYS
B
110
−1.283
7.290
−14.595
1.00
34.52
N
ATOM
1165
CA
LYS
B
110
−1.941
6.463
−15.617
1.00
35.64
C
ATOM
1166
CB
LYS
B
110
−3.318
7.045
−15.923
1.00
35.09
C
ATOM
1167
CG
LYS
B
110
−4.199
6.200
−16.799
1.00
36.36
C
ATOM
1168
CD
LYS
B
110
−5.256
7.078
−17.360
1.00
37.52
C
ATOM
1169
CE
LYS
B
110
−6.197
6.331
−18.301
1.00
43.96
C
ATOM
1170
NZ
LYS
B
110
−6.738
5.149
−17.583
1.00
45.73
N
ATOM
1171
C
LYS
B
110
−1.073
6.512
−16.889
1.00
35.81
C
ATOM
1172
O
LYS
B
110
−0.677
7.581
−17.306
1.00
34.99
O
ATOM
1173
N
VAL
B
111
−0.765
5.344
−17.453
1.00
36.14
N
ATOM
1174
CA
VAL
B
111
−0.183
5.256
−18.790
1.00
37.37
C
ATOM
1175
CB
VAL
B
111
0.595
3.969
−18.988
1.00
38.40
C
ATOM
1176
CG1
VAL
B
111
1.096
3.874
−20.451
1.00
40.21
C
ATOM
1177
CG2
VAL
B
111
1.746
3.934
−18.025
1.00
39.38
C
ATOM
1178
C
VAL
B
111
−1.329
5.314
−19.766
1.00
37.36
C
ATOM
1179
O
VAL
B
111
−2.230
4.493
−19.737
1.00
37.69
O
ATOM
1180
N
GLU
B
112
−1.367
6.331
−20.596
1.00
36.83
N
ATOM
1181
CA
GLU
B
112
−2.436
6.329
−21.550
1.00
37.26
C
ATOM
1182
CB
GLU
B
112
−3.334
7.501
−21.290
1.00
37.53
C
ATOM
1183
CG
GLU
B
112
−4.730
7.186
−21.687
1.00
42.45
C
ATOM
1184
CD
GLU
B
112
−5.518
8.434
−21.769
1.00
47.91
C
ATOM
1185
OE1
GLU
B
112
−6.665
8.423
−21.268
1.00
49.77
O
ATOM
1186
OE2
GLU
B
112
−4.951
9.421
−22.317
1.00
47.40
O
ATOM
1187
C
GLU
B
112
−1.915
6.361
−22.986
1.00
36.04
C
ATOM
1188
O
GLU
B
112
−1.497
7.415
−23.484
1.00
34.78
O
ATOM
1189
N
GLY
B
113
−1.920
5.204
−23.644
1.00
35.37
N
ATOM
1190
CA
GLY
B
113
−1.239
5.135
−24.935
1.00
33.99
C
ATOM
1191
C
GLY
B
113
0.262
5.420
−24.706
1.00
32.46
C
ATOM
1192
O
GLY
B
113
0.895
4.810
−23.819
1.00
33.59
O
ATOM
1193
N
PRO
B
114
0.842
6.341
−25.484
1.00
30.86
N
ATOM
1194
CA
PRO
B
114
2.254
6.728
−25.432
1.00
30.15
C
ATOM
1195
CB
PRO
B
114
2.491
7.285
−26.845
1.00
30.38
C
ATOM
1196
CG
PRO
B
114
1.188
7.915
−27.171
1.00
30.21
C
ATOM
1197
CD
PRO
B
114
0.128
7.066
−26.553
1.00
31.78
C
ATOM
1198
C
PRO
B
114
2.584
7.817
−24.386
1.00
28.89
C
ATOM
1199
O
PRO
B
114
3.733
8.284
−24.323
1.00
27.26
O
ATOM
1200
N
LEU
B
115
1.603
8.178
−23.538
1.00
27.32
N
ATOM
1201
CA
LEU
B
115
1.751
9.275
−22.578
1.00
27.63
C
ATOM
1202
CB
LEU
B
115
0.833
10.464
−22.938
1.00
26.73
C
ATOM
1203
CG
LEU
B
115
0.951
11.005
−24.372
1.00
28.81
C
ATOM
1204
CD1
LEU
B
115
−0.120
12.044
−24.555
1.00
28.14
C
ATOM
1205
CD2
LEU
B
115
2.323
11.667
−24.558
1.00
27.61
C
ATOM
1206
C
LEU
B
115
1.456
8.803
−21.149
1.00
27.69
C
ATOM
1207
O
LEU
B
115
0.695
7.849
−20.937
1.00
28.97
O
ATOM
1208
N
CYS
B
116
2.077
9.493
−20.204
1.00
28.03
N
ATOM
1209
CA
CYS
B
116
1.923
9.240
−18.787
1.00
27.99
C
ATOM
1210
CB
CYS
B
116
3.288
8.988
−18.165
1.00
28.84
C
ATOM
1211
SG
CYS
B
116
3.202
8.685
−16.342
1.00
32.13
S
ATOM
1212
C
CYS
B
116
1.275
10.452
−18.147
1.00
28.28
C
ATOM
1213
O
CYS
B
116
1.700
11.596
−18.392
1.00
27.83
O
ATOM
1214
N
ILE
B
117
0.204
10.204
−17.354
1.00
27.49
N
ATOM
1215
CA
ILE
B
117
−0.572
11.279
−16.710
1.00
26.02
C
ATOM
1216
CB
ILE
B
117
−2.093
11.221
−17.073
1.00
26.73
C
ATOM
1217
CG1
ILE
B
117
−2.262
11.134
−18.605
1.00
27.69
C
ATOM
1218
CD1
ILE
B
117
−3.458
10.398
−19.049
1.00
28.54
C
ATOM
1219
CG2
ILE
B
117
−2.878
12.453
−16.465
1.00
25.95
C
ATOM
1220
C
ILE
B
117
−0.391
11.052
−15.192
1.00
24.22
C
ATOM
1221
O
ILE
B
117
−0.574
9.957
−14.719
1.00
26.21
O
ATOM
1222
N
ARG
B
118
0.002
12.093
−14.495
1.00
24.83
N
ATOM
1223
CA
ARG
B
118
0.151
12.069
−13.050
1.00
24.60
C
ATOM
1224
CB
ARG
B
118
1.625
12.324
−12.676
1.00
26.12
C
ATOM
1225
CG
ARG
B
118
2.554
11.240
−13.053
1.00
29.98
C
ATOM
1226
CD
ARG
B
118
3.976
11.644
−12.680
1.00
36.27
C
ATOM
1227
NE
ARG
B
118
4.833
10.487
−12.835
1.00
43.72
N
ATOM
1228
CZ
ARG
B
118
5.739
10.363
−13.792
1.00
48.66
C
ATOM
1229
NH1
ARG
B
118
5.935
11.371
−14.654
1.00
50.62
N
ATOM
1230
NH2
ARG
B
118
6.456
9.235
−13.879
1.00
50.32
N
ATOM
1231
C
ARG
B
118
−0.648
13.195
−12.465
1.00
23.69
C
ATOM
1232
O
ARG
B
118
−0.738
14.276
−13.030
1.00
22.96
O
ATOM
1233
N
ILE
B
119
−1.170
12.992
−11.254
1.00
24.51
N
ATOM
1234
CA
ILE
B
119
−1.918
14.071
−10.630
1.00
23.38
C
ATOM
1235
CB
ILE
B
119
−3.379
14.189
−11.220
1.00
25.08
C
ATOM
1236
CG1
ILE
B
119
−4.168
15.391
−10.625
1.00
24.01
C
ATOM
1237
CD1
ILE
B
119
−5.698
15.456
−11.077
1.00
24.74
C
ATOM
1238
CG2
ILE
B
119
−4.097
12.864
−11.167
1.00
26.19
C
ATOM
1239
C
ILE
B
119
−1.927
13.744
−9.149
1.00
22.60
C
ATOM
1240
O
ILE
B
119
−1.861
12.601
−8.768
1.00
23.10
O
ATOM
1241
N
ASP
B
120
−1.893
14.786
−8.349
1.00
22.84
N
ATOM
1242
CA
ASP
B
120
−2.059
14.611
−6.892
1.00
24.58
C
ATOM
1243
CB
ASP
B
120
−1.358
15.710
−6.147
1.00
23.29
C
ATOM
1244
CG
ASP
B
120
−1.252
15.431
−4.633
1.00
25.72
C
ATOM
1245
OD1
ASP
B
120
−1.856
14.473
−4.136
1.00
26.52
O
ATOM
1246
OD2
ASP
B
120
−0.495
16.173
−3.961
1.00
27.39
O
ATOM
1247
C
ASP
B
120
−3.561
14.713
−6.580
1.00
22.94
C
ATOM
1248
O
ASP
B
120
−4.145
15.773
−6.725
1.00
23.18
O
ATOM
1249
N
GLN
B
121
−4.127
13.597
−6.196
1.00
23.75
N
ATOM
1250
CA
GLN
B
121
−5.534
13.493
−5.718
1.00
24.41
C
ATOM
1251
CB
GLN
B
121
−5.888
12.008
−5.498
1.00
23.59
C
ATOM
1252
CG
GLN
B
121
−7.357
11.742
−4.999
1.00
24.61
C
ATOM
1253
CD
GLN
B
121
−7.689
10.313
−4.820
1.00
25.20
C
ATOM
1254
OE1
GLN
B
121
−6.826
9.468
−4.792
1.00
24.43
O
ATOM
1255
NE2
GLN
B
121
−8.996
10.017
−4.688
1.00
28.25
N
ATOM
1256
C
GLN
B
121
−5.863
14.386
−4.487
1.00
24.49
C
ATOM
1257
O
GLN
B
121
−7.026
14.736
−4.267
1.00
24.40
O
ATOM
1258
N
ALA
B
122
−4.842
14.834
−3.740
1.00
25.85
N
ATOM
1259
CA
ALA
B
122
−5.058
15.623
−2.509
1.00
24.80
C
ATOM
1260
CB
ALA
B
122
−3.813
15.587
−1.658
1.00
25.27
C
ATOM
1261
C
ALA
B
122
−5.372
17.049
−2.846
1.00
25.48
C
ATOM
1262
O
ALA
B
122
−5.871
17.837
−2.014
1.00
23.88
O
ATOM
1263
N
ILE
B
123
−5.033
17.457
−4.065
1.00
25.50
N
ATOM
1264
CA
ILE
B
123
−5.136
18.876
−4.370
1.00
26.71
C
ATOM
1265
CB
ILE
B
123
−4.088
19.273
−5.469
1.00
27.03
C
ATOM
1266
CG1
ILE
B
123
−2.664
19.148
−4.895
1.00
28.82
C
ATOM
1267
CD1
ILE
B
123
−2.252
20.255
−3.962
1.00
28.25
C
ATOM
1268
CG2
ILE
B
123
−4.368
20.704
−6.006
1.00
29.25
C
ATOM
1269
C
ILE
B
123
−6.541
19.345
−4.791
1.00
28.30
C
ATOM
1270
O
ILE
B
123
−7.114
18.843
−5.810
1.00
28.00
O
ATOM
1271
N
MET
B
124
−7.059
20.359
−4.072
1.00
27.99
N
ATOM
1272
CA
MET
B
124
−8.433
20.849
−4.267
1.00
30.20
C
ATOM
1273
CB
MET
B
124
−9.407
20.226
−3.257
1.00
28.85
C
ATOM
1274
CG
MET
B
124
−9.245
18.768
−3.159
1.00
30.84
C
ATOM
1275
SD
MET
B
124
−10.621
18.153
−2.165
1.00
33.91
S
ATOM
1276
CE
MET
B
124
−10.006
16.631
−1.750
1.00
24.31
C
ATOM
1277
C
MET
B
124
−8.505
22.326
−4.146
1.00
31.04
C
ATOM
1278
O
MET
B
124
−7.600
22.948
−3.608
1.00
31.15
O
ATOM
1279
N
ASP
B
125
−9.577
22.892
−4.694
1.00
33.33
N
ATOM
1280
CA
ASP
B
125
−9.940
24.291
−4.503
1.00
34.92
C
ATOM
1281
CB
ASP
B
125
−10.269
24.509
−3.012
1.00
36.08
C
ATOM
1282
CG
ASP
B
125
−11.451
23.718
−2.579
1.00
38.58
C
ATOM
1283
OD1
ASP
B
125
−12.498
23.851
−3.285
1.00
46.09
O
ATOM
1284
OD2
ASP
B
125
−11.342
22.965
−1.572
1.00
41.80
O
ATOM
1285
C
ASP
B
125
−8.930
25.325
−4.949
1.00
35.72
C
ATOM
1286
O
ASP
B
125
−8.958
26.442
−4.455
1.00
36.05
O
ATOM
1287
N
LYS
B
126
−8.045
24.987
−5.880
1.00
34.36
N
ATOM
1288
CA
LYS
B
126
−7.079
25.938
−6.355
1.00
34.46
C
ATOM
1289
CB
LYS
B
126
−5.654
25.347
−6.229
1.00
35.61
C
ATOM
1290
CG
LYS
B
126
−5.123
25.518
−4.749
1.00
35.45
C
ATOM
1291
CD
LYS
B
126
−4.231
24.371
−4.247
1.00
41.21
C
ATOM
1292
CE
LYS
B
126
−4.235
24.232
−2.709
1.00
40.11
C
ATOM
1293
NZ
LYS
B
126
−5.023
23.010
−2.047
1.00
39.60
N
ATOM
1294
C
LYS
B
126
−7.410
26.445
−7.763
1.00
35.16
C
ATOM
1295
O
LYS
B
126
−8.172
25.801
−8.495
1.00
34.91
O
ATOM
1296
N
ASN
B
127
−6.917
27.635
−8.091
1.00
34.53
N
ATOM
1297
CA
ASN
B
127
−6.852
28.104
−9.463
1.00
35.83
C
ATOM
1298
CB
ASN
B
127
−6.784
29.634
−9.482
1.00
36.09
C
ATOM
1299
CG
ASN
B
127
−8.059
30.259
−8.963
1.00
39.59
C
ATOM
1300
OD1
ASN
B
127
−9.151
29.895
−9.403
1.00
42.15
O
ATOM
1301
ND2
ASN
B
127
−7.935
31.181
−8.010
1.00
41.71
N
ATOM
1302
C
ASN
B
127
−5.608
27.460
−10.123
1.00
35.83
C
ATOM
1303
O
ASN
B
127
−4.471
27.660
−9.646
1.00
35.54
O
ATOM
1304
N
ILE
B
128
−5.838
26.643
−11.153
1.00
34.49
N
ATOM
1305
CA
ILE
B
128
−4.762
25.838
−11.739
1.00
34.62
C
ATOM
1306
CB
ILE
B
128
−5.119
24.306
−11.680
1.00
34.79
C
ATOM
1307
CG1
ILE
B
128
−5.265
23.784
−10.233
1.00
32.44
C
ATOM
1308
CD1
ILE
B
128
−3.957
23.744
−9.465
1.00
36.65
C
ATOM
1309
CG2
ILE
B
128
−4.116
23.458
−12.496
1.00
33.81
C
ATOM
1310
C
ILE
B
128
−4.571
26.280
−13.192
1.00
34.82
C
ATOM
1311
O
ILE
B
128
−5.550
26.529
−13.892
1.00
35.00
O
ATOM
1312
N
MET
B
129
−3.314
26.404
−13.643
1.00
35.61
N
ATOM
1313
CA
MET
B
129
−2.996
26.814
−15.021
1.00
34.86
C
ATOM
1314
CB
MET
B
129
−2.261
28.179
−15.048
1.00
35.13
C
ATOM
1315
CG
MET
B
129
−1.751
28.640
−16.447
1.00
35.56
C
ATOM
1316
SD
MET
B
129
−3.035
29.030
−17.670
1.00
38.68
S
ATOM
1317
CE
MET
B
129
−3.538
30.686
−17.157
1.00
41.92
C
ATOM
1318
C
MET
B
129
−2.130
25.742
−15.712
1.00
34.42
C
ATOM
1319
O
MET
B
129
−1.032
25.415
−15.221
1.00
33.25
O
ATOM
1320
N
LEU
B
130
−2.612
25.201
−16.832
1.00
33.00
N
ATOM
1321
CA
LEU
B
130
−1.798
24.222
−17.574
1.00
32.79
C
ATOM
1322
CB
LEU
B
130
−2.667
23.270
−18.395
1.00
33.33
C
ATOM
1323
CG
LEU
B
130
−3.805
22.507
−17.746
1.00
34.39
C
ATOM
1324
CD1
LEU
B
130
−4.218
21.298
−18.640
1.00
35.78
C
ATOM
1325
CD2
LEU
B
130
−3.454
22.026
−16.355
1.00
33.03
C
ATOM
1326
C
LEU
B
130
−0.867
25.000
−18.501
1.00
31.81
C
ATOM
1327
O
LEU
B
130
−1.316
25.839
−19.251
1.00
31.56
O
ATOM
1328
N
LYS
B
131
0.425
24.706
−18.407
1.00
31.06
N
ATOM
1329
CA
LYS
B
131
1.487
25.276
−19.233
1.00
30.62
C
ATOM
1330
CB
LYS
B
131
2.465
26.072
−18.367
1.00
31.05
C
ATOM
1331
CG
LYS
B
131
1.907
27.398
−17.944
1.00
33.09
C
ATOM
1332
CD
LYS
B
131
2.876
28.133
−17.055
1.00
35.17
C
ATOM
1333
CE
LYS
B
131
2.199
29.374
−16.485
1.00
38.38
C
ATOM
1334
NZ
LYS
B
131
3.249
30.258
−15.877
1.00
39.16
N
ATOM
1335
C
LYS
B
131
2.215
24.125
−19.926
1.00
29.36
C
ATOM
1336
O
LYS
B
131
2.375
23.043
−19.365
1.00
29.14
O
ATOM
1337
N
ALA
B
132
2.596
24.318
−21.183
1.00
27.61
N
ATOM
1338
CA
ALA
B
132
3.286
23.232
−21.881
1.00
26.94
C
ATOM
1339
CB
ALA
B
132
2.302
22.385
−22.757
1.00
24.90
C
ATOM
1340
C
ALA
B
132
4.443
23.733
−22.737
1.00
26.64
C
ATOM
1341
O
ALA
B
132
4.454
24.875
−23.193
1.00
26.99
O
ATOM
1342
N
ASN
B
133
5.405
22.846
−22.933
1.00
27.01
N
ATOM
1343
CA
ASN
B
133
6.506
23.033
−23.898
1.00
27.23
C
ATOM
1344
CB
ASN
B
133
7.863
22.830
−23.177
1.00
28.41
C
ATOM
1345
CG
ASN
B
133
8.211
24.006
−22.255
1.00
30.04
C
ATOM
1346
OD1
ASN
B
133
7.344
24.721
−21.806
1.00
31.04
O
ATOM
1347
ND2
ASN
B
133
9.489
24.210
−21.993
1.00
34.78
N
ATOM
1348
C
ASN
B
133
6.293
22.000
−25.026
1.00
27.01
C
ATOM
1349
O
ASN
B
133
6.084
20.793
−24.784
1.00
25.65
O
ATOM
1350
N
PHE
B
134
6.295
22.469
−26.277
1.00
28.15
N
ATOM
1351
CA
PHE
B
134
5.929
21.577
−27.349
1.00
29.30
C
ATOM
1352
CB
PHE
B
134
4.400
21.283
−27.328
1.00
30.21
C
ATOM
1353
CG
PHE
B
134
3.533
22.520
−27.414
1.00
32.57
C
ATOM
1354
CD1
PHE
B
134
3.094
23.009
−28.647
1.00
33.22
C
ATOM
1355
CE1
PHE
B
134
2.312
24.154
−28.704
1.00
32.79
C
ATOM
1356
CZ
PHE
B
134
1.955
24.809
−27.541
1.00
33.90
C
ATOM
1357
CE2
PHE
B
134
2.401
24.324
−26.305
1.00
32.40
C
ATOM
1358
CD2
PHE
B
134
3.165
23.197
−26.257
1.00
31.50
C
ATOM
1359
C
PHE
B
134
6.329
22.201
−28.682
1.00
29.84
C
ATOM
1360
O
PHE
B
134
6.534
23.409
−28.792
1.00
30.16
O
ATOM
1361
N
SER
B
135
6.419
21.375
−29.710
1.00
31.15
N
ATOM
1362
CA
SER
B
135
6.679
21.941
−31.053
1.00
32.23
C
ATOM
1363
CB
SER
B
135
7.628
21.052
−31.812
1.00
32.51
C
ATOM
1364
OG
SER
B
135
7.036
19.812
−32.002
1.00
33.57
O
ATOM
1365
C
SER
B
135
5.386
22.073
−31.827
1.00
33.12
C
ATOM
1366
O
SER
B
135
4.420
21.371
−31.537
1.00
31.51
O
ATOM
1367
N
VAL
B
136
5.389
22.959
−32.839
1.00
34.96
N
ATOM
1368
CA
VAL
B
136
4.225
23.143
−33.685
1.00
36.92
C
ATOM
1369
CB
VAL
B
136
3.385
24.440
−33.371
1.00
37.96
C
ATOM
1370
CG1
VAL
B
136
2.815
24.423
−31.922
1.00
37.33
C
ATOM
1371
CG2
VAL
B
136
4.185
25.652
−33.544
1.00
38.33
C
ATOM
1372
C
VAL
B
136
4.701
23.143
−35.116
1.00
38.73
C
ATOM
1373
O
VAL
B
136
5.834
23.563
−35.409
1.00
38.26
O
ATOM
1374
N
ILE
B
137
3.882
22.554
−35.969
1.00
40.79
N
ATOM
1375
CA
ILE
B
137
4.031
22.698
−37.411
1.00
44.55
C
ATOM
1376
CB
ILE
B
137
4.633
21.429
−38.099
1.00
44.67
C
ATOM
1377
CG1
ILE
B
137
3.919
20.174
−37.651
1.00
45.11
C
ATOM
1378
CD1
ILE
B
137
4.421
18.930
−38.328
1.00
49.18
C
ATOM
1379
CG2
ILE
B
137
6.109
21.293
−37.822
1.00
47.14
C
ATOM
1380
C
ILE
B
137
2.633
22.973
−37.940
1.00
45.83
C
ATOM
1381
O
ILE
B
137
1.658
22.408
−37.420
1.00
46.23
O
ATOM
1382
N
PHE
B
138
2.539
23.867
−38.932
1.00
48.16
N
ATOM
1383
CA
PHE
B
138
1.279
24.178
−39.629
1.00
50.06
C
ATOM
1384
CB
PHE
B
138
0.792
22.974
−40.474
1.00
51.11
C
ATOM
1385
CG
PHE
B
138
1.852
22.411
−41.398
1.00
53.72
C
ATOM
1386
CD1
PHE
B
138
2.183
21.054
−41.358
1.00
57.35
C
ATOM
1387
CE1
PHE
B
138
3.189
20.518
−42.204
1.00
57.68
C
ATOM
1388
CZ
PHE
B
138
3.865
21.353
−43.080
1.00
55.86
C
ATOM
1389
CE2
PHE
B
138
3.545
22.720
−43.124
1.00
57.45
C
ATOM
1390
CD2
PHE
B
138
2.543
23.242
−42.286
1.00
55.69
C
ATOM
1391
C
PHE
B
138
0.210
24.607
−38.630
1.00
50.34
C
ATOM
1392
O
PHE
B
138
−0.923
24.093
−38.663
1.00
50.82
O
ATOM
1393
N
ASP
B
139
0.598
25.525
−37.741
1.00
50.41
N
ATOM
1394
CA
ASP
B
139
−0.252
26.037
−36.637
1.00
50.56
C
ATOM
1395
CB
ASP
B
139
−1.150
27.178
−37.125
1.00
52.14
C
ATOM
1396
CG
ASP
B
139
−0.371
28.481
−37.289
1.00
54.55
C
ATOM
1397
OD1
ASP
B
139
0.301
28.897
−36.307
1.00
57.23
O
ATOM
1398
OD2
ASP
B
139
−0.409
29.066
−38.398
0.50
56.46
O
ATOM
1399
C
ASP
B
139
−1.004
25.031
−35.770
1.00
49.51
C
ATOM
1400
O
ASP
B
139
−2.110
25.289
−35.243
1.00
49.37
O
ATOM
1401
N
ARG
B
140
−0.355
23.891
−35.580
1.00
47.68
N
ATOM
1402
CA
ARG
B
140
−0.920
22.771
−34.875
1.00
46.64
C
ATOM
1403
CB
ARG
B
140
−1.361
21.736
−35.917
1.00
47.18
C
ATOM
1404
CG
ARG
B
140
−1.906
20.430
−35.365
1.00
50.69
C
ATOM
1405
CD
ARG
B
140
−1.832
19.264
−36.415
1.00
52.62
C
ATOM
1406
NE
ARG
B
140
−0.462
19.002
−36.903
1.00
62.39
N
ATOM
1407
CZ
ARG
B
140
0.398
18.184
−36.289
1.00
65.34
C
ATOM
1408
NH1
ARG
B
140
0.013
17.558
−35.174
1.00
65.52
N
ATOM
1409
NH2
ARG
B
140
1.629
17.979
−36.783
1.00
64.58
N
ATOM
1410
C
ARG
B
140
0.174
22.207
−33.955
1.00
43.25
C
ATOM
1411
O
ARG
B
140
1.338
22.141
−34.342
1.00
41.78
O
ATOM
1412
N
LEU
B
141
−0.196
21.798
−32.742
1.00
40.18
N
ATOM
1413
CA
LEU
B
141
0.762
21.133
−31.854
1.00
38.38
C
ATOM
1414
CB
LEU
B
141
0.160
20.825
−30.457
1.00
37.77
C
ATOM
1415
CG
LEU
B
141
1.045
20.010
−29.474
1.00
36.52
C
ATOM
1416
CD1
LEU
B
141
0.754
20.416
−28.016
1.00
35.80
C
ATOM
1417
CD2
LEU
B
141
0.821
18.523
−29.680
1.00
30.24
C
ATOM
1418
C
LEU
B
141
1.214
19.859
−32.553
1.00
38.09
C
ATOM
1419
O
LEU
B
141
0.386
19.077
−33.023
1.00
37.31
O
ATOM
1420
N
GLU
B
142
2.535
19.671
−32.607
1.00
37.00
N
ATOM
1421
CA
GLU
B
142
3.161
18.538
−33.253
1.00
36.10
C
ATOM
1422
CB
GLU
B
142
4.385
19.046
−34.050
1.00
36.59
C
ATOM
1423
CG
GLU
B
142
5.078
17.967
−34.887
1.00
38.15
C
ATOM
1424
CD
GLU
B
142
6.464
18.401
−35.444
1.00
40.42
C
ATOM
1425
OE1
GLU
B
142
6.918
17.751
−36.404
1.00
44.80
O
ATOM
1426
OE2
GLU
B
142
7.121
19.345
−34.931
1.00
44.67
O
ATOM
1427
C
GLU
B
142
3.586
17.478
−32.219
1.00
33.59
C
ATOM
1428
O
GLU
B
142
3.102
16.346
−32.228
1.00
32.76
O
ATOM
1429
N
THR
B
143
4.496
17.869
−31.332
1.00
32.21
N
ATOM
1430
CA
THR
B
143
5.113
16.979
−30.334
1.00
30.26
C
ATOM
1431
CB
THR
B
143
6.590
16.671
−30.699
1.00
30.51
C
ATOM
1432
OG1
THR
B
143
6.584
15.914
−31.919
1.00
33.87
O
ATOM
1433
CG2
THR
B
143
7.249
15.807
−29.661
1.00
27.91
C
ATOM
1434
C
THR
B
143
5.091
17.688
−28.988
1.00
28.93
C
ATOM
1435
O
THR
B
143
5.617
18.800
−28.852
1.00
30.12
O
ATOM
1436
N
LEU
B
144
4.487
17.032
−28.002
1.00
27.73
N
ATOM
1437
CA
LEU
B
144
4.567
17.508
−26.616
1.00
26.43
C
ATOM
1438
CB
LEU
B
144
3.431
16.875
−25.801
1.00
26.11
C
ATOM
1439
CG
LEU
B
144
3.403
17.233
−24.313
1.00
24.22
C
ATOM
1440
CD1
LEU
B
144
3.063
18.671
−24.183
1.00
22.62
C
ATOM
1441
CD2
LEU
B
144
2.368
16.369
−23.592
1.00
25.40
C
ATOM
1442
C
LEU
B
144
5.925
17.128
−26.008
1.00
26.12
C
ATOM
1443
O
LEU
B
144
6.324
15.957
−26.032
1.00
26.26
O
ATOM
1444
N
ILE
B
145
6.594
18.101
−25.407
1.00
26.39
N
ATOM
1445
CA
ILE
B
145
7.767
17.789
−24.574
1.00
27.56
C
ATOM
1446
CB
ILE
B
145
8.807
18.976
−24.557
1.00
27.90
C
ATOM
1447
CG1
ILE
B
145
9.241
19.389
−25.990
1.00
31.80
C
ATOM
1448
CD1
ILE
B
145
9.501
18.216
−26.807
1.00
32.94
C
ATOM
1449
CG2
ILE
B
145
10.021
18.674
−23.598
1.00
27.03
C
ATOM
1450
C
ILE
B
145
7.278
17.493
−23.132
1.00
26.46
C
ATOM
1451
O
ILE
B
145
7.527
16.432
−22.576
1.00
25.81
O
ATOM
1452
N
LEU
B
146
6.530
18.428
−22.568
1.00
26.06
N
ATOM
1453
CA
LEU
B
146
6.041
18.267
−21.202
1.00
26.05
C
ATOM
1454
CB
LEU
B
146
7.173
18.571
−20.208
1.00
24.89
C
ATOM
1455
CG
LEU
B
146
6.931
18.388
−18.678
1.00
26.17
C
ATOM
1456
CD1
LEU
B
146
6.582
16.951
−18.314
1.00
25.01
C
ATOM
1457
CD2
LEU
B
146
8.135
18.936
−17.871
1.00
27.73
C
ATOM
1458
C
LEU
B
146
4.890
19.191
−20.970
1.00
24.78
C
ATOM
1459
O
LEU
B
146
4.935
20.345
−21.394
1.00
26.29
O
ATOM
1460
N
LEU
B
147
3.863
18.723
−20.243
1.00
24.66
N
ATOM
1461
CA
LEU
B
147
2.797
19.643
−19.856
1.00
23.39
C
ATOM
1462
CB
LEU
B
147
1.441
19.193
−20.441
1.00
23.05
C
ATOM
1463
CG
LEU
B
147
0.225
20.095
−20.123
1.00
24.92
C
ATOM
1464
CD1
LEU
B
147
−0.772
19.974
−21.269
1.00
24.09
C
ATOM
1465
CD2
LEU
B
147
−0.444
19.655
−18.790
1.00
25.78
C
ATOM
1466
C
LEU
B
147
2.752
19.524
−18.346
1.00
23.23
C
ATOM
1467
O
LEU
B
147
2.810
18.426
−17.860
1.00
23.78
O
ATOM
1468
N
ARG
B
148
2.610
20.634
−17.638
1.00
24.18
N
ATOM
1469
CA
ARG
B
148
2.443
20.592
−16.171
1.00
25.22
C
ATOM
1470
CB
ARG
B
148
3.744
20.991
−15.459
1.00
23.74
C
ATOM
1471
CG
ARG
B
148
4.731
19.806
−15.393
1.00
24.24
C
ATOM
1472
CD
ARG
B
148
6.127
20.136
−14.793
1.00
24.73
C
ATOM
1473
NE
ARG
B
148
6.742
18.845
−14.478
1.00
26.57
N
ATOM
1474
CZ
ARG
B
148
7.951
18.685
−13.915
1.00
27.32
C
ATOM
1475
NH1
ARG
B
148
8.675
19.731
−13.582
1.00
27.44
N
ATOM
1476
NH2
ARG
B
148
8.397
17.473
−13.660
1.00
26.04
N
ATOM
1477
C
ARG
B
148
1.327
21.521
−15.719
1.00
25.27
C
ATOM
1478
O
ARG
B
148
1.089
22.525
−16.348
1.00
26.12
O
ATOM
1479
N
ALA
B
149
0.732
21.216
−14.560
1.00
27.06
N
ATOM
1480
CA
ALA
B
149
−0.365
22.016
−14.035
1.00
26.93
C
ATOM
1481
CB
ALA
B
149
−1.557
21.094
−13.669
1.00
25.27
C
ATOM
1482
C
ALA
B
149
0.140
22.794
−12.817
1.00
27.42
C
ATOM
1483
O
ALA
B
149
0.668
22.201
−11.875
1.00
26.74
O
ATOM
1484
N
PHE
B
150
−0.011
24.108
−12.845
1.00
28.46
N
ATOM
1485
CA
PHE
B
150
0.541
24.969
−11.779
1.00
31.48
C
ATOM
1486
CB
PHE
B
150
1.476
26.039
−12.378
1.00
30.90
C
ATOM
1487
CG
PHE
B
150
2.683
25.461
−13.023
1.00
31.68
C
ATOM
1488
CD1
PHE
B
150
2.642
25.053
−14.369
1.00
31.92
C
ATOM
1489
CE1
PHE
B
150
3.777
24.515
−14.992
1.00
31.87
C
ATOM
1490
CZ
PHE
B
150
4.963
24.346
−14.254
1.00
31.46
C
ATOM
1491
CE2
PHE
B
150
4.996
24.724
−12.907
1.00
35.16
C
ATOM
1492
CD2
PHE
B
150
3.864
25.283
−12.294
1.00
32.53
C
ATOM
1493
C
PHE
B
150
−0.523
25.681
−10.979
1.00
32.52
C
ATOM
1494
O
PHE
B
150
−1.468
26.207
−11.536
1.00
33.40
O
ATOM
1495
N
THR
B
151
−0.344
25.709
−9.671
1.00
34.98
N
ATOM
1496
CA
THR
B
151
−1.181
26.568
−8.824
1.00
36.44
C
ATOM
1497
CB
THR
B
151
−1.101
26.201
−7.334
1.00
34.71
C
ATOM
1498
OG1
THR
B
151
0.205
26.513
−6.846
1.00
34.94
O
ATOM
1499
CG2
THR
B
151
−1.306
24.732
−7.167
1.00
35.77
C
ATOM
1500
C
THR
B
151
−0.693
27.978
−8.994
1.00
38.85
C
ATOM
1501
O
THR
B
151
0.368
28.212
−9.580
1.00
38.32
O
ATOM
1502
N
GLU
B
152
−1.473
28.927
−8.484
1.00
42.00
N
ATOM
1503
CA
GLU
B
152
−1.139
30.341
−8.597
1.00
44.30
C
ATOM
1504
CB
GLU
B
152
−2.230
31.168
−7.951
1.00
45.82
C
ATOM
1505
CG
GLU
B
152
−3.314
31.579
−8.878
1.00
48.98
C
ATOM
1506
CD
GLU
B
152
−4.434
32.252
−8.130
1.00
51.85
C
ATOM
1507
OE1
GLU
B
152
−4.303
32.390
−6.903
1.00
52.93
O
ATOM
1508
OE2
GLU
B
152
−5.445
32.619
−8.752
1.00
54.82
O
ATOM
1509
C
GLU
B
152
0.186
30.680
−7.952
1.00
44.72
C
ATOM
1510
O
GLU
B
152
0.841
31.641
−8.347
1.00
45.93
O
ATOM
1511
N
GLU
B
153
0.567
29.881
−6.961
1.00
45.12
N
ATOM
1512
CA
GLU
B
153
1.817
30.034
−6.242
1.00
45.17
C
ATOM
1513
CB
GLU
B
153
1.669
29.415
−4.855
1.00
46.29
C
ATOM
1514
CG
GLU
B
153
0.191
29.411
−4.346
1.00
51.61
C
ATOM
1515
CD
GLU
B
153
−0.230
30.758
−3.760
1.00
58.99
C
ATOM
1516
OE1
GLU
B
153
0.679
31.558
−3.403
1.00
61.45
O
ATOM
1517
OE2
GLU
B
153
−1.462
31.023
−3.653
1.00
61.26
O
ATOM
1518
C
GLU
B
153
2.979
29.367
−6.992
1.00
44.04
C
ATOM
1519
O
GLU
B
153
4.143
29.417
−6.535
1.00
43.59
O
ATOM
1520
N
GLY
B
154
2.675
28.728
−8.131
1.00
41.32
N
ATOM
1521
CA
GLY
B
154
3.724
28.130
−8.934
1.00
37.57
C
ATOM
1522
C
GLY
B
154
4.036
26.702
−8.539
1.00
36.03
C
ATOM
1523
O
GLY
B
154
5.054
26.151
−8.942
1.00
35.84
O
ATOM
1524
N
ALA
B
155
3.182
26.072
−7.740
1.00
33.82
N
ATOM
1525
CA
ALA
B
155
3.465
24.653
−7.375
1.00
32.57
C
ATOM
1526
CB
ALA
B
155
2.925
24.332
−6.013
1.00
32.09
C
ATOM
1527
C
ALA
B
155
2.865
23.701
−8.439
1.00
31.21
C
ATOM
1528
O
ALA
B
155
1.803
24.000
−8.987
1.00
32.00
O
ATOM
1529
N
ILE
B
156
3.544
22.579
−8.704
1.00
30.83
N
ATOM
1530
CA
ILE
B
156
3.093
21.593
−9.732
1.00
29.85
C
ATOM
1531
CB
ILE
B
156
4.257
20.837
−10.408
1.00
29.30
C
ATOM
1532
CG1
ILE
B
156
5.185
21.822
−11.123
1.00
30.27
C
ATOM
1533
CD1
ILE
B
156
6.673
21.342
−11.257
1.00
24.87
C
ATOM
1534
CG2
ILE
B
156
3.732
19.766
−11.402
1.00
30.34
C
ATOM
1535
C
ILE
B
156
2.168
20.588
−9.094
1.00
29.67
C
ATOM
1536
O
ILE
B
156
2.477
20.002
−8.031
1.00
28.50
O
ATOM
1537
N
VAL
B
157
0.999
20.401
−9.710
1.00
28.52
N
ATOM
1538
CA
VAL
B
157
0.035
19.457
−9.155
1.00
29.03
C
ATOM
1539
CB
VAL
B
157
−1.210
20.203
−8.605
1.00
28.67
C
ATOM
1540
CG1
VAL
B
157
−0.805
21.289
−7.551
1.00
29.30
C
ATOM
1541
CG2
VAL
B
157
−2.015
20.844
−9.723
1.00
28.06
C
ATOM
1542
C
VAL
B
157
−0.395
18.326
−10.108
1.00
28.97
C
ATOM
1543
O
VAL
B
157
−1.082
17.409
−9.684
1.00
29.30
O
ATOM
1544
N
GLY
B
158
0.037
18.405
−11.383
1.00
28.12
N
ATOM
1545
CA
GLY
B
158
−0.251
17.387
−12.380
1.00
27.35
C
ATOM
1546
C
GLY
B
158
0.715
17.552
−13.554
1.00
26.84
C
ATOM
1547
O
GLY
B
158
1.297
18.625
−13.730
1.00
25.99
O
ATOM
1548
N
GLU
B
159
0.931
16.466
−14.290
1.00
27.11
N
ATOM
1549
CA
GLU
B
159
1.705
16.564
−15.543
1.00
28.08
C
ATOM
1550
CB
GLU
B
159
3.218
16.605
−15.275
1.00
27.46
C
ATOM
1551
CG
GLU
B
159
3.852
15.305
−15.222
1.00
30.14
C
ATOM
1552
CD
GLU
B
159
5.361
15.328
−14.806
1.00
30.39
C
ATOM
1553
OE1
GLU
B
159
5.908
14.231
−14.822
1.00
33.34
O
ATOM
1554
OE2
GLU
B
159
5.948
16.375
−14.425
1.00
32.04
O
ATOM
1555
C
GLU
B
159
1.361
15.466
−16.559
1.00
27.20
C
ATOM
1556
O
GLU
B
159
0.757
14.462
−16.226
1.00
27.15
O
ATOM
1557
N
ILE
B
160
1.694
15.741
−17.823
1.00
27.13
N
ATOM
1558
CA
ILE
B
160
1.587
14.755
−18.883
1.00
27.82
C
ATOM
1559
CB
ILE
B
160
0.478
15.135
−19.891
1.00
28.16
C
ATOM
1560
CG1
ILE
B
160
−0.874
15.160
−19.168
1.00
26.78
C
ATOM
1561
CD1
ILE
B
160
−1.939
15.991
−19.916
1.00
27.37
C
ATOM
1562
CG2
ILE
B
160
0.390
14.107
−21.028
1.00
26.30
C
ATOM
1563
C
ILE
B
160
2.983
14.739
−19.516
1.00
27.85
C
ATOM
1564
O
ILE
B
160
3.518
15.785
−19.859
1.00
26.40
O
ATOM
1565
N
SER
B
161
3.589
13.569
−19.559
1.00
28.39
N
ATOM
1566
CA
SER
B
161
4.891
13.446
−20.194
1.00
30.42
C
ATOM
1567
CB
SER
B
161
6.019
13.335
−19.158
1.00
29.53
C
ATOM
1568
OG
SER
B
161
5.705
12.327
−18.230
1.00
36.43
O
ATOM
1569
C
SER
B
161
4.891
12.216
−21.092
1.00
30.22
C
ATOM
1570
O
SER
B
161
4.212
11.225
−20.815
1.00
29.26
O
ATOM
1571
N
PRO
B
162
5.653
12.292
−22.198
1.00
31.73
N
ATOM
1572
CA
PRO
B
162
5.830
11.168
−23.108
1.00
33.40
C
ATOM
1573
CB
PRO
B
162
6.620
11.787
−24.278
1.00
33.86
C
ATOM
1574
CG
PRO
B
162
6.244
13.258
−24.215
1.00
34.21
C
ATOM
1575
CD
PRO
B
162
6.298
13.505
−22.706
1.00
31.95
C
ATOM
1576
C
PRO
B
162
6.604
10.061
−22.459
1.00
34.81
C
ATOM
1577
O
PRO
B
162
7.528
10.343
−21.712
1.00
35.86
O
ATOM
1578
N
LEU
B
163
6.202
8.819
−22.718
1.00
36.44
N
ATOM
1579
CA
LEU
B
163
6.904
7.630
−22.250
1.00
40.34
C
ATOM
1580
CB
LEU
B
163
5.974
6.431
−22.203
1.00
40.13
C
ATOM
1581
CG
LEU
B
163
4.712
6.559
−21.340
1.00
42.63
C
ATOM
1582
CD1
LEU
B
163
3.831
5.395
−21.657
1.00
43.88
C
ATOM
1583
CD2
LEU
B
163
5.133
6.493
−19.879
1.00
46.62
C
ATOM
1584
C
LEU
B
163
8.064
7.304
−23.202
1.00
42.84
C
ATOM
1585
O
LEU
B
163
7.864
7.201
−24.420
1.00
42.13
O
ATOM
1586
N
PRO
B
164
9.269
7.100
−22.634
1.00
45.85
N
ATOM
1587
CA
PRO
B
164
10.548
6.943
−23.375
1.00
47.72
C
ATOM
1588
CB
PRO
B
164
11.519
6.449
−22.297
1.00
47.76
C
ATOM
1589
CG
PRO
B
164
10.921
6.900
−21.004
1.00
48.29
C
ATOM
1590
CD
PRO
B
164
9.429
6.889
−21.184
1.00
45.64
C
ATOM
1591
C
PRO
B
164
10.428
5.855
−24.422
1.00
49.11
C
ATOM
1592
O
PRO
B
164
10.863
6.022
−25.593
1.00
50.40
O
ATOM
1593
N
SER
B
165
9.806
4.760
−23.985
1.00
50.00
N
ATOM
1594
CA
SER
B
165
9.705
3.526
−24.738
1.00
50.56
C
ATOM
1595
CB
SER
B
165
9.385
2.399
−23.779
1.00
50.90
C
ATOM
1596
OG
SER
B
165
8.001
2.416
−23.479
1.00
51.74
O
ATOM
1597
C
SER
B
165
8.651
3.547
−25.847
1.00
50.55
C
ATOM
1598
O
SER
B
165
8.291
2.493
−26.384
1.00
51.11
O
ATOM
1599
N
PHE
B
166
8.129
4.720
−26.188
1.00
49.55
N
ATOM
1600
CA
PHE
B
166
7.297
4.812
−27.372
1.00
48.18
C
ATOM
1601
CB
PHE
B
166
5.913
5.364
−27.074
1.00
48.72
C
ATOM
1602
CG
PHE
B
166
4.950
4.328
−26.515
1.00
50.30
C
ATOM
1603
CD1
PHE
B
166
3.954
3.777
−27.318
1.00
52.19
C
ATOM
1604
CE1
PHE
B
166
3.045
2.834
−26.811
1.00
53.48
C
ATOM
1605
CZ
PHE
B
166
3.139
2.431
−25.480
1.00
52.84
C
ATOM
1606
CE2
PHE
B
166
4.123
2.993
−24.657
1.00
51.29
C
ATOM
1607
CD2
PHE
B
166
5.020
3.928
−25.178
1.00
51.96
C
ATOM
1608
C
PHE
B
166
8.029
5.623
−28.425
1.00
47.26
C
ATOM
1609
O
PHE
B
166
8.808
6.516
−28.089
1.00
46.10
O
ATOM
1610
N
PRO
B
167
7.814
5.284
−29.715
1.00
46.43
N
ATOM
1611
CA
PRO
B
167
8.561
6.016
−30.748
1.00
45.41
C
ATOM
1612
CB
PRO
B
167
8.412
5.128
−31.984
1.00
45.90
C
ATOM
1613
CG
PRO
B
167
7.006
4.463
−31.803
1.00
46.91
C
ATOM
1614
CD
PRO
B
167
6.894
4.265
−30.275
1.00
45.94
C
ATOM
1615
C
PRO
B
167
7.970
7.416
−30.995
1.00
44.77
C
ATOM
1616
O
PRO
B
167
8.647
8.278
−31.586
1.00
45.20
O
ATOM
1617
N
GLY
B
168
6.729
7.654
−30.545
1.00
42.28
N
ATOM
1618
CA
GLY
B
168
6.100
8.961
−30.762
1.00
38.80
C
ATOM
1619
C
GLY
B
168
4.652
9.017
−30.289
1.00
36.63
C
ATOM
1620
O
GLY
B
168
4.144
8.066
−29.741
1.00
35.45
O
ATOM
1621
N
HIS
B
169
3.998
10.148
−30.497
1.00
35.02
N
ATOM
1622
CA
HIS
B
169
2.574
10.257
−30.146
1.00
34.10
C
ATOM
1623
CB
HIS
B
169
2.430
10.713
−28.678
1.00
32.49
C
ATOM
1624
CG
HIS
B
169
3.112
12.018
−28.401
1.00
30.56
C
ATOM
1625
ND1
HIS
B
169
4.370
12.092
−27.835
1.00
28.47
N
ATOM
1626
CE1
HIS
B
169
4.745
13.365
−27.779
1.00
27.07
C
ATOM
1627
NE2
HIS
B
169
3.758
14.116
−28.244
1.00
26.23
N
ATOM
1628
CD2
HIS
B
169
2.735
13.298
−28.656
1.00
26.61
C
ATOM
1629
C
HIS
B
169
1.995
11.315
−31.050
1.00
33.97
C
ATOM
1630
O
HIS
B
169
2.737
12.034
−31.732
1.00
34.14
O
ATOM
1631
N
THR
B
170
0.672
11.472
−31.016
1.00
33.87
N
ATOM
1632
CA
THR
B
170
0.032
12.498
−31.835
1.00
34.49
C
ATOM
1633
CB
THR
B
170
−0.951
11.856
−32.841
1.00
35.29
C
ATOM
1634
OG1
THR
B
170
−2.138
11.488
−32.134
1.00
38.23
O
ATOM
1635
CG2
THR
B
170
−0.340
10.570
−33.492
1.00
34.81
C
ATOM
1636
C
THR
B
170
−0.744
13.511
−30.985
1.00
33.67
C
ATOM
1637
O
THR
B
170
−0.985
13.293
−29.780
1.00
32.49
O
ATOM
1638
N
ILE
B
171
−1.123
14.609
−31.616
1.00
32.84
N
ATOM
1639
CA
ILE
B
171
−2.019
15.577
−30.986
1.00
33.37
C
ATOM
1640
CB
ILE
B
171
−2.458
16.719
−31.968
1.00
33.99
C
ATOM
1641
CG1
ILE
B
171
−3.157
17.840
−31.181
1.00
33.44
C
ATOM
1642
CD1
ILE
B
171
−3.493
19.085
−31.943
1.00
32.95
C
ATOM
1643
CG2
ILE
B
171
−3.320
16.164
−33.168
1.00
34.46
C
ATOM
1644
C
ILE
B
171
−3.248
14.895
−30.379
1.00
32.88
C
ATOM
1645
O
ILE
B
171
−3.825
15.377
−29.383
1.00
32.45
O
ATOM
1646
N
GLU
B
172
−3.673
13.775
−30.957
1.00
32.23
N
ATOM
1647
CA
GLU
B
172
−4.881
13.160
−30.431
1.00
32.31
C
ATOM
1648
CB
GLU
B
172
−5.553
12.253
−31.434
1.00
33.12
C
ATOM
1649
CG
GLU
B
172
−5.931
12.970
−32.772
1.00
38.08
C
ATOM
1650
CD
GLU
B
172
−7.034
14.096
−32.699
1.00
42.24
C
ATOM
1651
OE1
GLU
B
172
−7.962
14.120
−31.828
1.00
38.52
O
ATOM
1652
OE2
GLU
B
172
−6.976
14.957
−33.605
1.00
44.85
O
ATOM
1653
C
GLU
B
172
−4.575
12.439
−29.117
1.00
31.00
C
ATOM
1654
O
GLU
B
172
−5.427
12.354
−28.221
1.00
29.39
O
ATOM
1655
N
ASP
B
173
−3.364
11.925
−28.994
1.00
29.29
N
ATOM
1656
CA
ASP
B
173
−2.957
11.312
−27.728
1.00
28.81
C
ATOM
1657
CB
ASP
B
173
−1.597
10.654
−27.827
1.00
28.63
C
ATOM
1658
CG
ASP
B
173
−1.591
9.462
−28.738
1.00
30.62
C
ATOM
1659
OD1
ASP
B
173
−2.461
8.581
−28.601
1.00
29.41
O
ATOM
1660
OD2
ASP
B
173
−0.660
9.403
−29.549
1.00
33.78
O
ATOM
1661
C
ASP
B
173
−2.880
12.394
−26.684
1.00
27.22
C
ATOM
1662
O
ASP
B
173
−3.223
12.156
−25.524
1.00
29.09
O
ATOM
1663
N
VAL
B
174
−2.390
13.553
−27.090
1.00
26.94
N
ATOM
1664
CA
VAL
B
174
−2.212
14.683
−26.195
1.00
27.05
C
ATOM
1665
CB
VAL
B
174
−1.431
15.823
−26.851
1.00
27.03
C
ATOM
1666
CG1
VAL
B
174
−1.453
17.050
−25.954
1.00
27.31
C
ATOM
1667
CG2
VAL
B
174
0.046
15.419
−27.117
1.00
28.19
C
ATOM
1668
C
VAL
B
174
−3.594
15.143
−25.715
1.00
27.12
C
ATOM
1669
O
VAL
B
174
−3.845
15.343
−24.519
1.00
24.96
O
ATOM
1670
N
LYS
B
175
−4.523
15.267
−26.650
1.00
25.83
N
ATOM
1671
CA
LYS
B
175
−5.874
15.649
−26.236
1.00
26.01
C
ATOM
1672
CB
LYS
B
175
−6.749
15.904
−27.458
1.00
26.17
C
ATOM
1673
CG
LYS
B
175
−6.739
17.324
−27.834
1.00
30.35
C
ATOM
1674
CD
LYS
B
175
−6.102
17.480
−29.128
1.00
38.18
C
ATOM
1675
CE
LYS
B
175
−7.142
17.623
−30.145
1.00
37.08
C
ATOM
1676
NZ
LYS
B
175
−7.550
19.051
−30.104
1.00
42.61
N
ATOM
1677
C
LYS
B
175
−6.542
14.661
−25.292
1.00
25.19
C
ATOM
1678
O
LYS
B
175
−7.220
15.074
−24.345
1.00
26.66
O
ATOM
1679
N
ASN
B
176
−6.414
13.358
−25.543
1.00
23.95
N
ATOM
1680
CA
ASN
B
176
−6.974
12.363
−24.636
1.00
23.14
C
ATOM
1681
CB
ASN
B
176
−6.557
10.938
−25.058
1.00
24.94
C
ATOM
1682
CG
ASN
B
176
−7.206
10.470
−26.375
1.00
26.18
C
ATOM
1683
OD1
ASN
B
176
−8.233
11.005
−26.802
1.00
29.88
O
ATOM
1684
ND2
ASN
B
176
−6.606
9.452
−26.994
1.00
29.47
N
ATOM
1685
C
ASN
B
176
−6.446
12.572
−23.184
1.00
23.69
C
ATOM
1686
O
ASN
B
176
−7.234
12.592
−22.206
1.00
22.87
O
ATOM
1687
N
ALA
B
177
−5.119
12.682
−23.064
1.00
22.91
N
ATOM
1688
CA
ALA
B
177
−4.442
12.879
−21.767
1.00
23.94
C
ATOM
1689
CB
ALA
B
177
−2.902
12.772
−21.924
1.00
25.51
C
ATOM
1690
C
ALA
B
177
−4.806
14.179
−21.085
1.00
22.98
C
ATOM
1691
O
ALA
B
177
−4.986
14.189
−19.863
1.00
23.61
O
ATOM
1692
N
ILE
B
178
−4.923
15.267
−21.832
1.00
23.01
N
ATOM
1693
CA
ILE
B
178
−5.391
16.554
−21.279
1.00
24.94
C
ATOM
1694
CB
ILE
B
178
−5.277
17.726
−22.315
1.00
23.97
C
ATOM
1695
CG1
ILE
B
178
−3.783
18.066
−22.574
1.00
25.98
C
ATOM
1696
CD1
ILE
B
178
−3.585
19.202
−23.573
1.00
27.04
C
ATOM
1697
CG2
ILE
B
178
−5.957
18.997
−21.792
1.00
24.69
C
ATOM
1698
C
ILE
B
178
−6.823
16.495
−20.696
1.00
25.65
C
ATOM
1699
O
ILE
B
178
−7.076
16.967
−19.583
1.00
26.20
O
ATOM
1700
N
GLY
B
179
−7.741
15.872
−21.421
1.00
24.86
N
ATOM
1701
CA
GLY
B
179
−9.067
15.626
−20.868
1.00
25.64
C
ATOM
1702
C
GLY
B
179
−9.022
14.827
−19.572
1.00
26.53
C
ATOM
1703
O
GLY
B
179
−9.759
15.131
−18.648
1.00
27.05
O
ATOM
1704
N
VAL
B
180
−8.181
13.778
−19.488
1.00
27.64
N
ATOM
1705
CA
VAL
B
180
−8.096
12.989
−18.230
1.00
26.49
C
ATOM
1706
CB
VAL
B
180
−7.242
11.709
−18.330
1.00
27.34
C
ATOM
1707
CG1
VAL
B
180
−6.987
11.099
−16.920
1.00
27.00
C
ATOM
1708
CG2
VAL
B
180
−7.918
10.674
−19.251
1.00
26.03
C
ATOM
1709
C
VAL
B
180
−7.571
13.854
−17.088
1.00
26.25
C
ATOM
1710
O
VAL
B
180
−8.148
13.836
−15.964
1.00
26.42
O
ATOM
1711
N
LEU
B
181
−6.511
14.607
−17.353
1.00
25.79
N
ATOM
1712
CA
LEU
B
181
−5.949
15.522
−16.345
1.00
26.04
C
ATOM
1713
CB
LEU
B
181
−4.587
16.119
−16.807
1.00
26.20
C
ATOM
1714
CG
LEU
B
181
−3.936
17.200
−15.923
1.00
26.41
C
ATOM
1715
CD1
LEU
B
181
−3.517
16.667
−14.581
1.00
22.34
C
ATOM
1716
CD2
LEU
B
181
−2.717
17.769
−16.620
1.00
24.16
C
ATOM
1717
C
LEU
B
181
−6.890
16.637
−15.881
1.00
26.68
C
ATOM
1718
O
LEU
B
181
−7.083
16.841
−14.654
1.00
26.04
O
ATOM
1719
N
ILE
B
182
−7.471
17.363
−16.835
1.00
26.09
N
ATOM
1720
CA
ILE
B
182
−8.388
18.436
−16.532
1.00
25.74
C
ATOM
1721
CB
ILE
B
182
−8.861
19.141
−17.805
1.00
26.51
C
ATOM
1722
CG1
ILE
B
182
−7.723
19.973
−18.396
1.00
24.82
C
ATOM
1723
CD1
ILE
B
182
−8.143
20.834
−19.674
1.00
25.81
C
ATOM
1724
CG2
ILE
B
182
−10.124
20.002
−17.515
1.00
27.97
C
ATOM
1725
C
ILE
B
182
−9.608
17.916
−15.775
1.00
26.63
C
ATOM
1726
O
ILE
B
182
−10.110
18.623
−14.867
1.00
26.56
O
ATOM
1727
N
GLY
B
183
−10.084
16.717
−16.143
1.00
25.84
N
ATOM
1728
CA
GLY
B
183
−11.280
16.150
−15.538
1.00
26.48
C
ATOM
1729
C
GLY
B
183
−10.999
15.788
−14.062
1.00
26.93
C
ATOM
1730
O
GLY
B
183
−11.881
15.926
−13.212
1.00
25.70
O
ATOM
1731
N
GLY
B
184
−9.780
15.311
−13.765
1.00
24.71
N
ATOM
1732
CA
GLY
B
184
−9.412
14.978
−12.383
1.00
27.81
C
ATOM
1733
C
GLY
B
184
−9.317
16.235
−11.536
1.00
27.95
C
ATOM
1734
O
GLY
B
184
−9.831
16.263
−10.411
1.00
29.12
O
ATOM
1735
N
LEU
B
185
−8.698
17.278
−12.075
1.00
27.43
N
ATOM
1736
CA
LEU
B
185
−8.556
18.574
−11.373
1.00
26.86
C
ATOM
1737
CB
LEU
B
185
−7.718
19.529
−12.199
1.00
26.76
C
ATOM
1738
CG
LEU
B
185
−6.203
19.174
−12.300
1.00
25.88
C
ATOM
1739
CD1
LEU
B
185
−5.629
20.023
−13.351
1.00
24.14
C
ATOM
1740
CD2
LEU
B
185
−5.470
19.340
−10.922
1.00
24.41
C
ATOM
1741
C
LEU
B
185
−9.938
19.230
−11.118
1.00
28.13
C
ATOM
1742
O
LEU
B
185
−10.205
19.698
−10.025
1.00
27.27
O
ATOM
1743
N
GLU
B
186
−10.779
19.302
−12.148
1.00
26.45
N
ATOM
1744
CA
GLU
B
186
−12.176
19.722
−12.017
1.00
28.86
C
ATOM
1745
CB
GLU
B
186
−12.913
19.596
−13.378
1.00
28.42
C
ATOM
1746
CG
GLU
B
186
−12.605
20.641
−14.405
1.00
31.60
C
ATOM
1747
CD
GLU
B
186
−13.303
20.308
−15.787
1.00
33.01
C
ATOM
1748
OE1
GLU
B
186
−13.747
19.131
−16.049
1.00
34.53
O
ATOM
1749
OE2
GLU
B
186
−13.393
21.253
−16.571
1.00
35.62
O
ATOM
1750
C
GLU
B
186
−12.918
18.895
−10.986
1.00
28.14
C
ATOM
1751
O
GLU
B
186
−13.594
19.470
−10.152
1.00
29.83
O
ATOM
1752
N
TRP
B
187
−12.839
17.557
−11.049
1.00
27.79
N
ATOM
1753
CA
TRP
B
187
−13.520
16.713
−10.106
1.00
29.99
C
ATOM
1754
CB
TRP
B
187
−13.187
15.237
−10.335
1.00
30.68
C
ATOM
1755
CG
TRP
B
187
−13.585
14.307
−9.227
1.00
34.71
C
ATOM
1756
CD1
TRP
B
187
−12.794
13.848
−8.167
1.00
35.56
C
ATOM
1757
NE1
TRP
B
187
−13.496
12.989
−7.373
1.00
36.67
N
ATOM
1758
CE2
TRP
B
187
−14.761
12.866
−7.899
1.00
38.56
C
ATOM
1759
CD2
TRP
B
187
−14.847
13.686
−9.060
1.00
35.87
C
ATOM
1760
CE3
TRP
B
187
−16.049
13.746
−9.774
1.00
34.89
C
ATOM
1761
CZ3
TRP
B
187
−17.098
13.013
−9.333
1.00
37.19
C
ATOM
1762
CH2
TRP
B
187
−16.998
12.205
−8.162
1.00
37.23
C
ATOM
1763
CZ2
TRP
B
187
−15.835
12.128
−7.435
1.00
38.41
C
ATOM
1764
C
TRP
B
187
−13.187
17.105
−8.646
1.00
29.34
C
ATOM
1765
O
TRP
B
187
−14.051
16.999
−7.782
1.00
26.13
O
ATOM
1766
N
ASN
B
188
−11.933
17.528
−8.418
1.00
29.25
N
ATOM
1767
CA
ASN
B
188
−11.426
18.015
−7.112
1.00
30.10
C
ATOM
1768
CB
ASN
B
188
−9.922
17.678
−6.960
1.00
30.98
C
ATOM
1769
CG
ASN
B
188
−9.691
16.346
−6.270
1.00
28.83
C
ATOM
1770
OD1
ASN
B
188
−10.634
15.706
−5.865
1.00
30.25
O
ATOM
1771
ND2
ASN
B
188
−8.427
15.909
−6.166
1.00
27.24
N
ATOM
1772
C
ASN
B
188
−11.645
19.483
−6.856
1.00
30.32
C
ATOM
1773
O
ASN
B
188
−10.987
20.074
−6.005
1.00
31.38
O
ATOM
1774
N
ASP
B
189
−12.578
20.083
−7.576
1.00
31.64
N
ATOM
1775
CA
ASP
B
189
−12.989
21.492
−7.404
1.00
31.66
C
ATOM
1776
CB
ASP
B
189
−13.739
21.693
−6.056
1.00
33.12
C
ATOM
1777
CG
ASP
B
189
−15.040
20.898
−6.016
1.00
37.29
C
ATOM
1778
OD1
ASP
B
189
−15.825
21.100
−6.970
1.00
38.57
O
ATOM
1779
OD2
ASP
B
189
−15.261
20.060
−5.084
1.00
40.54
O
ATOM
1780
C
ASP
B
189
−11.916
22.524
−7.602
1.00
32.43
C
ATOM
1781
O
ASP
B
189
−11.978
23.619
−7.028
1.00
30.55
O
ATOM
1782
N
ASN
B
190
−10.930
22.197
−8.443
1.00
30.63
N
ATOM
1783
CA
ASN
B
190
−10.001
23.204
−8.912
1.00
30.98
C
ATOM
1784
CB
ASN
B
190
−8.642
22.559
−9.244
1.00
29.41
C
ATOM
1785
CG
ASN
B
190
−8.039
21.837
−8.058
1.00
27.80
C
ATOM
1786
OD1
ASN
B
190
−7.559
22.467
−7.100
1.00
28.21
O
ATOM
1787
ND2
ASN
B
190
−8.069
20.507
−8.096
1.00
24.72
N
ATOM
1788
C
ASN
B
190
−10.590
23.894
−10.133
1.00
31.62
C
ATOM
1789
O
ASN
B
190
−11.320
23.270
−10.893
1.00
31.86
O
ATOM
1790
N
THR
B
191
−10.304
25.184
−10.298
1.00
32.87
N
ATOM
1791
CA
THR
B
191
−10.634
25.916
−11.509
1.00
34.75
C
ATOM
1792
CB
THR
B
191
−10.945
27.380
−11.169
1.00
35.55
C
ATOM
1793
OG1
THR
B
191
−12.062
27.415
−10.261
1.00
37.47
O
ATOM
1794
CG2
THR
B
191
−11.328
28.148
−12.411
1.00
37.42
C
ATOM
1795
C
THR
B
191
−9.437
25.837
−12.451
1.00
34.83
C
ATOM
1796
O
THR
B
191
−8.304
26.214
−12.070
1.00
35.55
O
ATOM
1797
N
VAL
B
192
−9.681
25.329
−13.661
1.00
34.58
N
ATOM
1798
CA
VAL
B
192
−8.604
25.019
−14.605
1.00
34.33
C
ATOM
1799
CB
VAL
B
192
−8.616
23.526
−15.076
1.00
33.53
C
ATOM
1800
CG1
VAL
B
192
−7.387
23.231
−16.021
1.00
34.55
C
ATOM
1801
CG2
VAL
B
192
−8.565
22.595
−13.908
1.00
31.05
C
ATOM
1802
C
VAL
B
192
−8.607
25.959
−15.788
1.00
35.32
C
ATOM
1803
O
VAL
B
192
−9.593
26.041
−16.515
1.00
35.56
O
ATOM
1804
N
ARG
B
193
−7.495
26.665
−15.987
1.00
35.84
N
ATOM
1805
CA
ARG
B
193
−7.252
27.415
−17.216
1.00
37.58
C
ATOM
1806
CB
ARG
B
193
−6.868
28.876
−16.900
1.00
37.82
C
ATOM
1807
CG
ARG
B
193
−8.073
29.733
−16.543
1.00
42.79
C
ATOM
1808
CD
ARG
B
193
−7.707
31.011
−15.825
1.00
50.50
C
ATOM
1809
NE
ARG
B
193
−8.639
31.231
−14.712
1.00
55.68
N
ATOM
1810
CZ
ARG
B
193
−8.545
30.633
−13.517
1.00
58.91
C
ATOM
1811
NH1
ARG
B
193
−7.546
29.763
−13.241
1.00
59.58
N
ATOM
1812
NH2
ARG
B
193
−9.454
30.908
−12.589
1.00
59.65
N
ATOM
1813
C
ARG
B
193
−6.111
26.775
−18.010
1.00
37.54
C
ATOM
1814
O
ARG
B
193
−5.287
26.058
−17.449
1.00
36.53
O
ATOM
1815
N
VAL
B
194
−6.055
27.093
−19.306
1.00
37.96
N
ATOM
1816
CA
VAL
B
194
−5.076
26.501
−20.232
1.00
37.55
C
ATOM
1817
CB
VAL
B
194
−5.834
25.611
−21.268
1.00
38.83
C
ATOM
1818
CG1
VAL
B
194
−5.025
25.322
−22.493
1.00
40.07
C
ATOM
1819
CG2
VAL
B
194
−6.213
24.302
−20.615
1.00
35.70
C
ATOM
1820
C
VAL
B
194
−4.301
27.662
−20.840
1.00
37.68
C
ATOM
1821
O
VAL
B
194
−4.886
28.739
−21.085
1.00
36.58
O
ATOM
1822
N
SER
B
195
−2.984
27.496
−21.020
1.00
36.31
N
ATOM
1823
CA
SER
B
195
−2.171
28.555
−21.584
1.00
35.49
C
ATOM
1824
CB
SER
B
195
−0.710
28.091
−21.710
1.00
35.57
C
ATOM
1825
OG
SER
B
195
−0.564
27.142
−22.752
1.00
33.21
O
ATOM
1826
C
SER
B
195
−2.770
28.982
−22.950
1.00
36.06
C
ATOM
1827
O
SER
B
195
−3.429
28.171
−23.634
1.00
34.56
O
ATOM
1828
N
LYS
B
196
−2.597
30.252
−23.306
1.00
36.20
N
ATOM
1829
CA
LYS
B
196
−3.116
30.760
−24.576
1.00
37.88
C
ATOM
1830
CB
LYS
B
196
−2.919
32.264
−24.713
1.00
38.69
C
ATOM
1831
CG
LYS
B
196
−3.804
33.084
−23.759
1.00
43.56
C
ATOM
1832
CD
LYS
B
196
−3.659
34.583
−24.100
1.00
49.67
C
ATOM
1833
CE
LYS
B
196
−4.059
35.504
−22.919
1.00
52.45
C
ATOM
1834
NZ
LYS
B
196
−2.985
35.632
−21.851
1.00
53.35
N
ATOM
1835
C
LYS
B
196
−2.448
30.060
−25.745
1.00
37.09
C
ATOM
1836
O
LYS
B
196
−3.068
29.898
−26.784
1.00
37.20
O
ATOM
1837
N
THR
B
197
−1.189
29.652
−25.576
1.00
36.42
N
ATOM
1838
CA
THR
B
197
−0.530
28.848
−26.612
1.00
36.69
C
ATOM
1839
CB
THR
B
197
0.992
28.707
−26.426
1.00
36.21
C
ATOM
1840
OG1
THR
B
197
1.260
28.069
−25.162
1.00
38.36
O
ATOM
1841
CG2
THR
B
197
1.678
30.046
−26.531
1.00
38.13
C
ATOM
1842
C
THR
B
197
−1.122
27.451
−26.718
1.00
35.35
C
ATOM
1843
O
THR
B
197
−1.297
26.953
−27.793
1.00
35.92
O
ATOM
1844
N
LEU
B
198
−1.418
26.809
−25.601
1.00
36.53
N
ATOM
1845
CA
LEU
B
198
−2.068
25.516
−25.657
1.00
36.92
C
ATOM
1846
CB
LEU
B
198
−2.180
24.876
−24.275
1.00
36.99
C
ATOM
1847
CG
LEU
B
198
−1.098
23.952
−23.729
1.00
33.23
C
ATOM
1848
CD1
LEU
B
198
−1.449
23.661
−22.274
1.00
33.04
C
ATOM
1849
CD2
LEU
B
198
−1.072
22.672
−24.603
1.00
29.08
C
ATOM
1850
C
LEU
B
198
−3.467
25.655
−26.256
1.00
39.11
C
ATOM
1851
O
LEU
B
198
−3.850
24.850
−27.092
1.00
38.44
O
ATOM
1852
N
GLN
B
199
−4.252
26.646
−25.830
1.00
41.80
N
ATOM
1853
CA
GLN
B
199
−5.572
26.806
−26.478
1.00
45.46
C
ATOM
1854
CB
GLN
B
199
−6.537
27.763
−25.752
1.00
45.75
C
ATOM
1855
CG
GLN
B
199
−6.008
29.085
−25.299
1.00
49.36
C
ATOM
1856
CD
GLN
B
199
−6.963
29.806
−24.295
1.00
50.29
C
ATOM
1857
OE1
GLN
B
199
−7.702
29.163
−23.540
1.00
54.54
O
ATOM
1858
NE2
GLN
B
199
−6.935
31.148
−24.303
1.00
55.26
N
ATOM
1859
C
GLN
B
199
−5.467
27.120
−27.970
1.00
45.02
C
ATOM
1860
O
GLN
B
199
−6.285
26.660
−28.731
1.00
45.85
O
ATOM
1861
N
ARG
B
200
−4.444
27.854
−28.388
1.00
45.93
N
ATOM
1862
CA
ARG
B
200
−4.258
28.142
−29.827
1.00
47.16
C
ATOM
1863
CB
ARG
B
200
−3.270
29.269
−30.062
1.00
47.37
C
ATOM
1864
CG
ARG
B
200
−2.927
29.415
−31.545
1.00
50.46
C
ATOM
1865
CD
ARG
B
200
−2.055
30.607
−31.841
1.00
54.16
C
ATOM
1866
NE
ARG
B
200
−1.831
30.736
−33.284
1.00
58.36
N
ATOM
1867
CZ
ARG
B
200
−0.821
31.406
−33.853
1.00
60.38
C
ATOM
1868
NH1
ARG
B
200
0.099
32.036
−33.117
1.00
59.70
N
ATOM
1869
NH2
ARG
B
200
−0.728
31.438
−35.178
1.00
61.24
N
ATOM
1870
C
ARG
B
200
−3.823
26.940
−30.663
1.00
47.23
C
ATOM
1871
O
ARG
B
200
−4.319
26.733
−31.775
1.00
47.03
O
ATOM
1872
N
PHE
B
201
−2.886
26.162
−30.134
1.00
47.51
N
ATOM
1873
CA
PHE
B
201
−2.210
25.130
−30.932
1.00
47.97
C
ATOM
1874
CB
PHE
B
201
−0.697
25.178
−30.715
1.00
46.65
C
ATOM
1875
CG
PHE
B
201
−0.060
26.428
−31.243
1.00
46.30
C
ATOM
1876
CD1
PHE
B
201
−0.158
26.752
−32.596
1.00
46.65
C
ATOM
1877
CE1
PHE
B
201
0.426
27.888
−33.096
1.00
44.92
C
ATOM
1878
CZ
PHE
B
201
1.120
28.730
−32.244
1.00
48.15
C
ATOM
1879
CE2
PHE
B
201
1.217
28.419
−30.878
1.00
46.43
C
ATOM
1880
CD2
PHE
B
201
0.632
27.280
−30.399
1.00
44.50
C
ATOM
1881
C
PHE
B
201
−2.753
23.736
−30.726
1.00
48.74
C
ATOM
1882
O
PHE
B
201
−2.597
22.864
−31.593
1.00
48.64
O
ATOM
1883
N
ALA
B
202
−3.370
23.508
−29.576
1.00
50.44
N
ATOM
1884
CA
ALA
B
202
−4.033
22.247
−29.341
1.00
53.42
C
ATOM
1885
CB
ALA
B
202
−3.728
21.709
−27.948
1.00
52.66
C
ATOM
1886
C
ALA
B
202
−5.543
22.370
−29.606
1.00
54.73
C
ATOM
1887
O
ALA
B
202
−6.238
21.374
−29.502
1.00
56.24
O
ATOM
1888
N
TRP
B
203
−6.011
23.586
−29.956
1.00
56.29
N
ATOM
1889
CA
TRP
B
203
−7.395
23.933
−30.455
1.00
56.94
C
ATOM
1890
CB
TRP
B
203
−8.380
24.142
−29.301
1.00
58.23
C
ATOM
1891
CG
TRP
B
203
−8.552
22.939
−28.504
1.00
59.56
C
ATOM
1892
CD1
TRP
B
203
−9.345
21.864
−28.804
1.00
61.53
C
ATOM
1893
NE1
TRP
B
203
−9.230
20.906
−27.822
1.00
62.77
N
ATOM
1894
CE2
TRP
B
203
−8.340
21.347
−26.873
1.00
62.01
C
ATOM
1895
CD2
TRP
B
203
−7.901
22.632
−27.269
1.00
61.50
C
ATOM
1896
CE3
TRP
B
203
−6.983
23.310
−26.460
1.00
62.77
C
ATOM
1897
CZ3
TRP
B
203
−6.547
22.698
−25.292
1.00
61.79
C
ATOM
1898
CH2
TRP
B
203
−7.013
21.418
−24.918
1.00
61.03
C
ATOM
1899
CZ2
TRP
B
203
−7.898
20.730
−25.690
1.00
60.64
C
ATOM
1900
C
TRP
B
203
−7.437
25.187
−31.366
1.00
57.77
C
ATOM
1901
O
TRP
B
203
−8.201
26.147
−31.186
1.00
57.76
O
ATOM
1902
OXT
TRP
B
203
−6.692
25.319
−32.339
1.00
58.42
O
ATOM
1903
N
HIS
D
56
34.592
2.339
9.216
1.00
64.66
N
ATOM
1904
CA
HIS
D
56
34.345
2.715
10.649
1.00
64.55
C
ATOM
1905
CB
HIS
D
56
35.029
1.705
11.625
1.00
65.47
C
ATOM
1906
CG
HIS
D
56
36.531
1.764
11.637
1.00
68.06
C
ATOM
1907
ND1
HIS
D
56
37.317
1.022
10.777
1.00
71.84
N
ATOM
1908
CE1
HIS
D
56
38.593
1.276
11.018
1.00
72.28
C
ATOM
1909
NE2
HIS
D
56
38.664
2.154
12.006
1.00
70.72
N
ATOM
1910
CD2
HIS
D
56
37.390
2.469
12.415
1.00
69.56
C
ATOM
1911
C
HIS
D
56
34.649
4.212
10.979
1.00
63.35
C
ATOM
1912
O
HIS
D
56
35.235
4.560
12.024
1.00
63.93
O
ATOM
1913
N
HIS
D
57
34.212
5.104
10.095
1.00
61.01
N
ATOM
1914
CA
HIS
D
57
34.497
6.533
10.244
1.00
58.95
C
ATOM
1915
CB
HIS
D
57
35.769
6.906
9.444
1.00
59.82
C
ATOM
1916
CG
HIS
D
57
36.783
5.797
9.346
1.00
62.98
C
ATOM
1917
ND1
HIS
D
57
36.602
4.683
8.545
1.00
66.61
N
ATOM
1918
CE1
HIS
D
57
37.641
3.872
8.672
1.00
67.08
C
ATOM
1919
NE2
HIS
D
57
38.490
4.417
9.528
1.00
67.51
N
ATOM
1920
CD2
HIS
D
57
37.979
5.622
9.961
1.00
66.43
C
ATOM
1921
C
HIS
D
57
33.300
7.267
9.654
1.00
55.91
C
ATOM
1922
O
HIS
D
57
32.887
6.931
8.536
1.00
56.18
O
ATOM
1923
N
HIS
D
58
32.694
8.230
10.355
1.00
51.42
N
ATOM
1924
CA
HIS
D
58
31.740
9.014
9.589
1.00
47.26
C
ATOM
1925
CB
HIS
D
58
30.404
9.340
10.238
1.00
48.71
C
ATOM
1926
CG
HIS
D
58
29.369
9.596
9.188
1.00
54.11
C
ATOM
1927
ND1
HIS
D
58
28.703
10.793
9.049
1.00
58.72
N
ATOM
1928
CE1
HIS
D
58
27.920
10.740
7.977
1.00
61.41
C
ATOM
1929
NE2
HIS
D
58
28.103
9.573
7.379
1.00
60.54
N
ATOM
1930
CD2
HIS
D
58
29.009
8.842
8.112
1.00
59.27
C
ATOM
1931
C
HIS
D
58
32.286
10.247
8.894
1.00
42.65
C
ATOM
1932
O
HIS
D
58
33.093
10.973
9.453
1.00
40.85
O
ATOM
1933
N
HIS
D
59
31.787
10.482
7.680
1.00
37.62
N
ATOM
1934
CA
HIS
D
59
32.120
11.671
6.915
1.00
33.38
C
ATOM
1935
CB
HIS
D
59
31.913
11.451
5.408
1.00
31.80
C
ATOM
1936
CG
HIS
D
59
32.889
10.495
4.815
1.00
30.00
C
ATOM
1937
ND1
HIS
D
59
34.093
10.904
4.271
1.00
26.51
N
ATOM
1938
CE1
HIS
D
59
34.761
9.837
3.865
1.00
28.12
C
ATOM
1939
NE2
HIS
D
59
34.015
8.765
4.067
1.00
27.17
N
ATOM
1940
CD2
HIS
D
59
32.845
9.148
4.679
1.00
28.48
C
ATOM
1941
C
HIS
D
59
31.362
12.894
7.336
1.00
32.02
C
ATOM
1942
O
HIS
D
59
31.849
13.970
7.117
1.00
32.51
O
ATOM
1943
N
MET
D
60
30.150
12.765
7.885
1.00
31.80
N
ATOM
1944
CA
MET
D
60
29.369
13.977
8.243
1.00
31.40
C
ATOM
1945
CB
MET
D
60
27.889
13.902
7.828
1.00
32.22
C
ATOM
1946
CG
MET
D
60
27.617
13.875
6.267
1.00
37.88
C
ATOM
1947
SD
MET
D
60
27.808
15.376
5.183
1.00
44.72
S
ATOM
1948
CE
MET
D
60
26.475
16.498
5.654
1.00
45.45
C
ATOM
1949
C
MET
D
60
29.501
14.277
9.760
1.00
29.90
C
ATOM
1950
O
MET
D
60
29.577
13.361
10.575
1.00
28.64
O
ATOM
1951
N
SER
D
61
29.535
15.557
10.109
1.00
30.29
N
ATOM
1952
CA
SER
D
61
29.588
15.983
11.499
1.00
30.76
C
ATOM
1953
CB
SER
D
61
29.925
17.460
11.570
1.00
30.74
C
ATOM
1954
OG
SER
D
61
28.848
18.250
11.070
1.00
29.96
O
ATOM
1955
C
SER
D
61
28.253
15.750
12.221
1.00
32.49
C
ATOM
1956
O
SER
D
61
28.206
15.601
13.460
1.00
32.22
O
ATOM
1957
N
GLY
D
62
27.173
15.744
11.452
1.00
33.25
N
ATOM
1958
CA
GLY
D
62
25.831
15.442
11.967
1.00
34.91
C
ATOM
1959
C
GLY
D
62
24.939
15.316
10.728
1.00
37.02
C
ATOM
1960
O
GLY
D
62
25.415
15.463
9.602
1.00
36.12
O
ATOM
1961
N
GLU
D
63
23.649
15.056
10.903
1.00
38.27
N
ATOM
1962
CA
GLU
D
63
22.778
15.047
9.723
1.00
41.05
C
ATOM
1963
CB
GLU
D
63
22.745
13.647
9.064
1.00
41.25
C
ATOM
1964
CG
GLU
D
63
21.929
12.590
9.806
1.00
44.88
C
ATOM
1965
CD
GLU
D
63
22.092
11.175
9.212
1.00
45.68
C
ATOM
1966
OE1
GLU
D
63
21.509
10.883
8.130
1.00
50.03
O
ATOM
1967
OE2
GLU
D
63
22.789
10.347
9.848
1.00
51.89
O
ATOM
1968
C
GLU
D
63
21.359
15.560
10.053
1.00
40.41
C
ATOM
1969
O
GLU
D
63
20.917
15.481
11.203
1.00
39.58
O
ATOM
1970
N
LYS
D
64
20.675
16.079
9.030
1.00
39.97
N
ATOM
1971
CA
LYS
D
64
19.253
16.453
9.124
1.00
39.55
C
ATOM
1972
CB
LYS
D
64
18.855
17.312
7.933
1.00
38.27
C
ATOM
1973
CG
LYS
D
64
19.498
18.676
7.978
1.00
37.25
C
ATOM
1974
CD
LYS
D
64
19.352
19.392
6.699
1.00
37.42
C
ATOM
1975
CE
LYS
D
64
19.582
20.874
6.890
1.00
40.00
C
ATOM
1976
NZ
LYS
D
64
19.659
21.591
5.597
1.00
41.12
N
ATOM
1977
C
LYS
D
64
18.447
15.173
9.226
1.00
39.27
C
ATOM
1978
O
LYS
D
64
18.598
14.260
8.428
1.00
40.43
O
ATOM
1979
N
THR
D
65
17.612
15.062
10.241
1.00
40.07
N
ATOM
1980
CA
THR
D
65
17.000
13.756
10.492
1.00
40.21
C
ATOM
1981
CB
THR
D
65
17.075
13.371
11.988
1.00
40.76
C
ATOM
1982
OG1
THR
D
65
16.660
14.502
12.769
1.00
42.99
O
ATOM
1983
CG2
THR
D
65
18.532
12.999
12.379
1.00
42.94
C
ATOM
1984
C
THR
D
65
15.543
13.715
10.026
1.00
38.61
C
ATOM
1985
O
THR
D
65
14.950
12.653
9.998
1.00
38.55
O
ATOM
1986
N
VAL
D
66
14.976
14.875
9.685
1.00
37.32
N
ATOM
1987
CA
VAL
D
66
13.577
14.945
9.213
1.00
36.16
C
ATOM
1988
CB
VAL
D
66
12.658
15.607
10.304
1.00
37.17
C
ATOM
1989
CG1
VAL
D
66
11.174
15.588
9.875
1.00
36.22
C
ATOM
1990
CG2
VAL
D
66
12.797
14.868
11.625
1.00
37.85
C
ATOM
1991
C
VAL
D
66
13.414
15.723
7.913
1.00
34.38
C
ATOM
1992
O
VAL
D
66
13.926
16.848
7.791
1.00
33.99
O
ATOM
1993
N
VAL
D
67
12.646
15.159
6.969
1.00
34.25
N
ATOM
1994
CA
VAL
D
67
12.330
15.843
5.687
1.00
33.06
C
ATOM
1995
CB
VAL
D
67
11.704
14.865
4.636
1.00
33.93
C
ATOM
1996
CG1
VAL
D
67
11.168
15.648
3.370
1.00
30.51
C
ATOM
1997
CG2
VAL
D
67
12.691
13.730
4.262
1.00
34.10
C
ATOM
1998
C
VAL
D
67
11.411
17.069
5.921
1.00
32.76
C
ATOM
1999
O
VAL
D
67
10.519
17.011
6.756
1.00
33.03
O
ATOM
2000
N
CYS
D
68
11.676
18.179
5.236
1.00
32.16
N
ATOM
2001
CA
CYS
D
68
10.907
19.397
5.407
1.00
32.44
C
ATOM
2002
CB
CYS
D
68
11.597
20.575
4.774
1.00
31.82
C
ATOM
2003
SG
CYS
D
68
10.774
22.098
5.030
1.00
33.61
S
ATOM
2004
C
CYS
D
68
9.550
19.203
4.723
1.00
32.88
C
ATOM
2005
O
CYS
D
68
9.476
19.154
3.491
1.00
30.62
O
ATOM
2006
N
LYS
D
69
8.484
19.090
5.519
1.00
33.15
N
ATOM
2007
CA
LYS
D
69
7.172
18.858
4.910
1.00
34.88
C
ATOM
2008
CB
LYS
D
69
6.157
18.270
5.917
1.00
35.34
C
ATOM
2009
CG
LYS
D
69
5.811
19.205
7.044
1.00
36.65
C
ATOM
2010
CD
LYS
D
69
4.712
18.618
7.967
1.00
37.03
C
ATOM
2011
CE
LYS
D
69
3.257
18.968
7.480
1.00
37.27
C
ATOM
2012
NZ
LYS
D
69
2.907
20.446
7.579
1.00
36.89
N
ATOM
2013
C
LYS
D
69
6.676
20.095
4.180
1.00
35.15
C
ATOM
2014
O
LYS
D
69
5.946
19.975
3.181
1.00
35.27
O
ATOM
2015
N
HIS
D
70
7.104
21.288
4.605
1.00
37.08
N
ATOM
2016
CA
HIS
D
70
6.813
22.498
3.813
1.00
38.20
C
ATOM
2017
CB
HIS
D
70
7.195
23.768
4.561
1.00
39.21
C
ATOM
2018
CG
HIS
D
70
6.402
23.956
5.819
1.00
43.73
C
ATOM
2019
ND1
HIS
D
70
6.986
24.109
7.059
1.00
46.35
N
ATOM
2020
CE1
HIS
D
70
6.045
24.214
7.979
1.00
47.53
C
ATOM
2021
NE2
HIS
D
70
4.869
24.094
7.387
1.00
49.18
N
ATOM
2022
CD2
HIS
D
70
5.063
23.940
6.035
1.00
46.48
C
ATOM
2023
C
HIS
D
70
7.467
22.438
2.441
1.00
38.73
C
ATOM
2024
O
HIS
D
70
6.829
22.759
1.422
1.00
39.48
O
ATOM
2025
N
TRP
D
71
8.725
21.994
2.397
1.00
38.01
N
ATOM
2026
CA
TRP
D
71
9.446
21.887
1.121
1.00
36.93
C
ATOM
2027
CB
TRP
D
71
10.920
21.482
1.360
1.00
36.60
C
ATOM
2028
CG
TRP
D
71
11.596
21.051
0.116
1.00
35.32
C
ATOM
2029
CD1
TRP
D
71
12.129
21.868
−0.845
1.00
36.20
C
ATOM
2030
NE1
TRP
D
71
12.666
21.117
−1.863
1.00
33.00
N
ATOM
2031
CE2
TRP
D
71
12.492
19.786
−1.575
1.00
33.99
C
ATOM
2032
CD2
TRP
D
71
11.801
19.706
−0.337
1.00
33.26
C
ATOM
2033
CE3
TRP
D
71
11.486
18.448
0.185
1.00
29.61
C
ATOM
2034
CZ3
TRP
D
71
11.830
17.336
−0.535
1.00
34.23
C
ATOM
2035
CH2
TRP
D
71
12.498
17.450
−1.790
1.00
34.83
C
ATOM
2036
CZ2
TRP
D
71
12.820
18.668
−2.319
1.00
32.77
C
ATOM
2037
C
TRP
D
71
8.754
20.885
0.194
1.00
37.16
C
ATOM
2038
O
TRP
D
71
8.694
21.086
−1.021
1.00
37.02
O
ATOM
2039
N
LEU
D
72
8.255
19.790
0.744
1.00
37.29
N
ATOM
2040
CA
LEU
D
72
7.503
18.834
−0.072
1.00
38.20
C
ATOM
2041
CB
LEU
D
72
6.952
17.721
0.795
1.00
37.67
C
ATOM
2042
CG
LEU
D
72
7.960
16.753
1.405
1.00
38.01
C
ATOM
2043
CD1
LEU
D
72
7.214
15.930
2.418
1.00
36.10
C
ATOM
2044
CD2
LEU
D
72
8.554
15.878
0.336
1.00
37.04
C
ATOM
2045
C
LEU
D
72
6.381
19.501
−0.894
1.00
38.76
C
ATOM
2046
O
LEU
D
72
6.122
19.104
−2.037
1.00
38.00
O
ATOM
2047
N
ARG
D
73
5.789
20.555
−0.332
1.00
39.92
N
ATOM
2048
CA
ARG
D
73
4.608
21.205
−0.903
1.00
41.93
C
ATOM
2049
CB
ARG
D
73
3.477
21.262
0.139
1.00
41.43
C
ATOM
2050
CG
ARG
D
73
3.054
19.908
0.710
1.00
41.64
C
ATOM
2051
CD
ARG
D
73
1.665
20.001
1.435
1.00
42.77
C
ATOM
2052
NE
ARG
D
73
0.577
20.306
0.489
1.00
41.40
N
ATOM
2053
CZ
ARG
D
73
−0.128
21.435
0.432
1.00
41.05
C
ATOM
2054
NH1
ARG
D
73
0.061
22.426
1.297
1.00
38.28
N
ATOM
2055
NH2
ARG
D
73
−1.048
21.575
−0.533
1.00
40.79
N
ATOM
2056
C
ARG
D
73
4.926
22.597
−1.457
1.00
43.33
C
ATOM
2057
O
ARG
D
73
4.018
23.377
−1.768
1.00
44.11
O
ATOM
2058
N
GLY
D
74
6.222
22.914
−1.564
1.00
44.01
N
ATOM
2059
CA
GLY
D
74
6.686
24.181
−2.145
1.00
45.02
C
ATOM
2060
C
GLY
D
74
6.470
25.382
−1.248
1.00
45.92
C
ATOM
2061
O
GLY
D
74
6.309
26.515
−1.713
1.00
46.72
O
ATOM
2062
N
LEU
D
75
6.445
25.149
0.051
1.00
46.34
N
ATOM
2063
CA
LEU
D
75
6.107
26.222
0.997
1.00
47.13
C
ATOM
2064
CB
LEU
D
75
4.934
25.777
1.885
1.00
46.90
C
ATOM
2065
CG
LEU
D
75
3.568
25.669
1.231
1.00
46.99
C
ATOM
2066
CD1
LEU
D
75
2.730
24.757
2.056
1.00
48.19
C
ATOM
2067
CD2
LEU
D
75
2.944
27.049
1.136
1.00
47.54
C
ATOM
2068
C
LEU
D
75
7.309
26.631
1.869
1.00
47.52
C
ATOM
2069
O
LEU
D
75
7.141
27.245
2.939
1.00
48.30
O
ATOM
2070
N
CYS
D
76
8.509
26.251
1.423
1.00
47.15
N
ATOM
2071
CA
CYS
D
76
9.741
26.554
2.151
1.00
47.29
C
ATOM
2072
CB
CYS
D
76
10.341
25.307
2.803
1.00
46.82
C
ATOM
2073
SG
CYS
D
76
11.782
25.664
3.833
1.00
44.67
S
ATOM
2074
C
CYS
D
76
10.736
27.187
1.201
1.00
47.45
C
ATOM
2075
O
CYS
D
76
11.029
26.650
0.125
1.00
47.30
O
ATOM
2076
N
LYS
D
77
11.231
28.342
1.639
1.00
48.56
N
ATOM
2077
CA
LYS
D
77
12.129
29.218
0.883
1.00
49.52
C
ATOM
2078
CB
LYS
D
77
11.691
30.695
1.055
1.00
50.19
C
ATOM
2079
CG
LYS
D
77
10.278
31.028
0.538
1.00
53.97
C
ATOM
2080
CD
LYS
D
77
10.225
30.845
−0.981
1.00
58.79
C
ATOM
2081
CE
LYS
D
77
9.050
29.979
−1.397
1.00
62.13
C
ATOM
2082
NZ
LYS
D
77
9.133
29.643
−2.858
1.00
64.34
N
ATOM
2083
C
LYS
D
77
13.584
29.101
1.377
1.00
48.54
C
ATOM
2084
O
LYS
D
77
14.485
29.711
0.788
1.00
48.99
O
ATOM
2085
N
LYS
D
78
13.787
28.351
2.466
1.00
47.21
N
ATOM
2086
CA
LYS
D
78
15.080
28.269
3.165
1.00
46.17
C
ATOM
2087
CB
LYS
D
78
14.865
27.778
4.588
1.00
45.59
C
ATOM
2088
CG
LYS
D
78
14.052
28.736
5.431
1.00
48.72
C
ATOM
2089
CD
LYS
D
78
13.535
28.042
6.657
1.00
51.08
C
ATOM
2090
CE
LYS
D
78
12.626
28.955
7.426
1.00
54.63
C
ATOM
2091
NZ
LYS
D
78
12.237
28.258
8.680
1.00
57.29
N
ATOM
2092
C
LYS
D
78
16.216
27.465
2.488
1.00
45.04
C
ATOM
2093
O
LYS
D
78
17.366
27.532
2.929
1.00
45.07
O
ATOM
2094
N
GLY
D
79
15.912
26.718
1.432
1.00
43.75
N
ATOM
2095
CA
GLY
D
79
16.935
25.956
0.712
1.00
42.63
C
ATOM
2096
C
GLY
D
79
17.814
25.108
1.629
1.00
41.82
C
ATOM
2097
O
GLY
D
79
17.323
24.490
2.582
1.00
41.57
O
ATOM
2098
N
ASP
D
80
19.118
25.104
1.346
1.00
41.32
N
ATOM
2099
CA
ASP
D
80
20.137
24.381
2.150
1.00
41.34
C
ATOM
2100
CB
ASP
D
80
21.551
24.566
1.548
1.00
40.65
C
ATOM
2101
CG
ASP
D
80
21.723
23.844
0.223
1.00
41.10
C
ATOM
2102
OD1
ASP
D
80
20.833
23.048
−0.171
1.00
41.81
O
ATOM
2103
OD2
ASP
D
80
22.763
24.061
−0.440
1.00
41.86
O
ATOM
2104
C
ASP
D
80
20.153
24.779
3.609
1.00
40.66
C
ATOM
2105
O
ASP
D
80
20.533
23.985
4.474
1.00
40.51
O
ATOM
2106
N
GLN
D
81
19.678
25.988
3.874
1.00
40.84
N
ATOM
2107
CA
GLN
D
81
19.728
26.572
5.205
1.00
40.62
C
ATOM
2108
CB
GLN
D
81
19.909
28.096
5.119
1.00
40.77
C
ATOM
2109
CG
GLN
D
81
21.305
28.536
4.655
1.00
41.97
C
ATOM
2110
CD
GLN
D
81
21.538
28.288
3.171
1.00
43.96
C
ATOM
2111
OE1
GLN
D
81
20.627
28.463
2.370
1.00
44.29
O
ATOM
2112
NE2
GLN
D
81
22.752
27.878
2.797
1.00
40.50
N
ATOM
2113
C
GLN
D
81
18.514
26.200
6.071
1.00
40.22
C
ATOM
2114
O
GLN
D
81
18.448
26.615
7.231
1.00
39.54
O
ATOM
2115
N
CYS
D
82
17.575
25.410
5.526
1.00
39.25
N
ATOM
2116
CA
CYS
D
82
16.459
24.923
6.329
1.00
38.42
C
ATOM
2117
CB
CYS
D
82
15.385
24.223
5.486
1.00
38.37
C
ATOM
2118
SG
CYS
D
82
13.883
23.896
6.491
1.00
38.87
S
ATOM
2119
C
CYS
D
82
16.962
23.975
7.411
1.00
38.75
C
ATOM
2120
O
CYS
D
82
17.970
23.296
7.235
1.00
38.23
O
ATOM
2121
N
GLU
D
83
16.260
23.945
8.534
1.00
38.22
N
ATOM
2122
CA
GLU
D
83
16.586
23.050
9.622
1.00
38.64
C
ATOM
2123
CB
GLU
D
83
15.717
23.407
10.845
1.00
38.85
C
ATOM
2124
CG
GLU
D
83
15.738
22.391
11.960
1.00
39.99
C
ATOM
2125
CD
GLU
D
83
14.765
22.732
13.111
1.00
43.45
C
ATOM
2126
OE1
GLU
D
83
14.146
23.834
13.100
1.00
49.61
O
ATOM
2127
OE2
GLU
D
83
14.624
21.882
14.025
1.00
47.89
O
ATOM
2128
C
GLU
D
83
16.364
21.615
9.174
1.00
36.61
C
ATOM
2129
O
GLU
D
83
16.969
20.663
9.694
1.00
36.20
O
ATOM
2130
N
PHE
D
84
15.448
21.458
8.218
1.00
35.98
N
ATOM
2131
CA
PHE
D
84
14.988
20.138
7.797
1.00
33.86
C
ATOM
2132
CB
PHE
D
84
13.445
20.073
7.860
1.00
34.81
C
ATOM
2133
CG
PHE
D
84
12.908
20.343
9.227
1.00
34.72
C
ATOM
2134
CD1
PHE
D
84
12.327
21.562
9.522
1.00
37.93
C
ATOM
2135
CE1
PHE
D
84
11.841
21.806
10.805
1.00
39.57
C
ATOM
2136
CZ
PHE
D
84
11.981
20.835
11.803
1.00
37.48
C
ATOM
2137
CE2
PHE
D
84
12.557
19.631
11.533
1.00
39.44
C
ATOM
2138
CD2
PHE
D
84
13.043
19.389
10.238
1.00
37.62
C
ATOM
2139
C
PHE
D
84
15.488
19.841
6.394
1.00
32.86
C
ATOM
2140
O
PHE
D
84
15.867
20.728
5.679
1.00
31.87
O
ATOM
2141
N
LEU
D
85
15.452
18.576
6.012
1.00
32.17
N
ATOM
2142
CA
LEU
D
85
16.090
18.146
4.793
1.00
32.87
C
ATOM
2143
CB
LEU
D
85
16.309
16.646
4.887
1.00
32.14
C
ATOM
2144
CG
LEU
D
85
16.987
15.995
3.686
1.00
32.65
C
ATOM
2145
CD1
LEU
D
85
18.475
16.518
3.562
1.00
30.51
C
ATOM
2146
CD2
LEU
D
85
16.905
14.484
3.898
1.00
32.51
C
ATOM
2147
C
LEU
D
85
15.234
18.444
3.563
1.00
34.15
C
ATOM
2148
O
LEU
D
85
14.022
18.140
3.554
1.00
33.04
O
ATOM
2149
N
HIS
D
86
15.865
19.006
2.527
1.00
33.66
N
ATOM
2150
CA
HIS
D
86
15.177
19.238
1.282
1.00
34.81
C
ATOM
2151
CB
HIS
D
86
15.456
20.639
0.786
1.00
34.31
C
ATOM
2152
CG
HIS
D
86
14.760
21.691
1.587
1.00
33.56
C
ATOM
2153
ND1
HIS
D
86
14.431
22.914
1.062
1.00
35.34
N
ATOM
2154
CE1
HIS
D
86
13.867
23.653
1.998
1.00
35.36
C
ATOM
2155
NE2
HIS
D
86
13.761
22.928
3.092
1.00
34.33
N
ATOM
2156
CD2
HIS
D
86
14.323
21.700
2.869
1.00
32.93
C
ATOM
2157
C
HIS
D
86
15.424
18.223
0.195
1.00
35.48
C
ATOM
2158
O
HIS
D
86
15.701
18.615
−0.934
1.00
36.99
O
ATOM
2159
N
GLU
D
87
15.339
16.938
0.533
1.00
36.60
N
ATOM
2160
CA
GLU
D
87
15.300
15.870
−0.461
1.00
38.04
C
ATOM
2161
CB
GLU
D
87
16.656
15.148
−0.598
1.00
38.88
C
ATOM
2162
CG
GLU
D
87
17.818
16.031
−1.075
1.00
41.12
C
ATOM
2163
CD
GLU
D
87
17.624
16.634
−2.476
1.00
45.48
C
ATOM
2164
OE1
GLU
D
87
16.697
16.215
−3.226
1.00
41.76
O
ATOM
2165
OE2
GLU
D
87
18.399
17.568
−2.803
1.00
45.80
O
ATOM
2166
C
GLU
D
87
14.230
14.862
−0.082
1.00
38.87
C
ATOM
2167
O
GLU
D
87
13.856
14.750
1.096
1.00
37.77
O
ATOM
2168
N
TYR
D
88
13.722
14.118
−1.058
1.00
40.40
N
ATOM
2169
CA
TYR
D
88
12.747
13.090
−0.695
1.00
42.60
C
ATOM
2170
CB
TYR
D
88
11.639
12.789
−1.767
1.00
43.58
C
ATOM
2171
CG
TYR
D
88
10.558
11.877
−1.139
1.00
46.74
C
ATOM
2172
CD1
TYR
D
88
9.714
12.348
−0.109
1.00
47.35
C
ATOM
2173
CE1
TYR
D
88
8.769
11.503
0.523
1.00
49.00
C
ATOM
2174
CZ
TYR
D
88
8.663
10.177
0.152
1.00
47.77
C
ATOM
2175
OH
TYR
D
88
7.779
9.314
0.784
1.00
47.83
O
ATOM
2176
CE2
TYR
D
88
9.506
9.679
−0.843
1.00
51.26
C
ATOM
2177
CD2
TYR
D
88
10.460
10.530
−1.482
1.00
49.05
C
ATOM
2178
C
TYR
D
88
13.410
11.825
−0.149
1.00
42.69
C
ATOM
2179
O
TYR
D
88
13.821
10.941
−0.900
1.00
43.66
O
ATOM
2180
N
ASP
D
89
13.461
11.710
1.169
1.00
42.43
N
ATOM
2181
CA
ASP
D
89
13.906
10.477
1.777
1.00
42.60
C
ATOM
2182
CB
ASP
D
89
15.119
10.778
2.648
1.00
42.36
C
ATOM
2183
CG
ASP
D
89
15.771
9.540
3.182
1.00
42.78
C
ATOM
2184
OD1
ASP
D
89
15.168
8.442
3.116
1.00
42.68
O
ATOM
2185
OD2
ASP
D
89
16.914
9.667
3.670
1.00
44.94
O
ATOM
2186
C
ASP
D
89
12.776
9.836
2.595
1.00
43.43
C
ATOM
2187
O
ASP
D
89
12.476
10.292
3.696
1.00
42.72
O
ATOM
2188
N
MET
D
90
12.179
8.762
2.069
1.00
44.28
N
ATOM
2189
CA
MET
D
90
10.995
8.143
2.686
1.00
47.28
C
ATOM
2190
CB
MET
D
90
10.397
7.019
1.805
1.00
46.57
C
ATOM
2191
CG
MET
D
90
11.272
5.745
1.686
1.00
50.99
C
ATOM
2192
SD
MET
D
90
10.600
4.293
0.770
1.00
55.26
S
ATOM
2193
CE
MET
D
90
10.460
4.964
−0.896
1.00
54.61
C
ATOM
2194
C
MET
D
90
11.283
7.639
4.105
1.00
46.07
C
ATOM
2195
O
MET
D
90
10.355
7.302
4.848
1.00
45.61
O
ATOM
2196
N
THR
D
91
12.570
7.594
4.466
1.00
44.61
N
ATOM
2197
CA
THR
D
91
12.987
7.061
5.747
1.00
43.51
C
ATOM
2198
CB
THR
D
91
14.350
6.254
5.648
1.00
44.59
C
ATOM
2199
OG1
THR
D
91
15.463
7.160
5.457
1.00
45.89
O
ATOM
2200
CG2
THR
D
91
14.305
5.201
4.517
1.00
44.25
C
ATOM
2201
C
THR
D
91
13.144
8.164
6.764
1.00
41.77
C
ATOM
2202
O
THR
D
91
13.354
7.894
7.948
1.00
42.02
O
ATOM
2203
N
LYS
D
92
13.073
9.406
6.306
1.00
38.80
N
ATOM
2204
CA
LYS
D
92
13.220
10.539
7.197
1.00
37.66
C
ATOM
2205
CB
LYS
D
92
14.428
11.401
6.773
1.00
37.27
C
ATOM
2206
CG
LYS
D
92
15.767
10.664
6.901
1.00
40.93
C
ATOM
2207
CD
LYS
D
92
16.930
11.547
6.425
1.00
37.83
C
ATOM
2208
CE
LYS
D
92
18.245
10.765
6.528
1.00
45.63
C
ATOM
2209
NZ
LYS
D
92
19.377
11.764
6.464
1.00
44.22
N
ATOM
2210
C
LYS
D
92
11.955
11.412
7.290
1.00
35.80
C
ATOM
2211
O
LYS
D
92
12.035
12.615
7.539
1.00
34.91
O
ATOM
2212
N
MET
D
93
10.792
10.805
7.099
1.00
34.90
N
ATOM
2213
CA
MET
D
93
9.547
11.588
7.032
1.00
33.48
C
ATOM
2214
CB
MET
D
93
8.496
10.843
6.180
1.00
33.76
C
ATOM
2215
CG
MET
D
93
8.850
10.843
4.652
1.00
29.06
C
ATOM
2216
SD
MET
D
93
8.662
12.469
3.962
1.00
28.76
S
ATOM
2217
CE
MET
D
93
6.963
12.472
3.449
1.00
36.37
C
ATOM
2218
C
MET
D
93
9.058
11.939
8.444
1.00
33.59
C
ATOM
2219
O
MET
D
93
9.258
11.123
9.349
1.00
32.16
O
ATOM
2220
N
PRO
D
94
8.462
13.153
8.632
1.00
33.50
N
ATOM
2221
CA
PRO
D
94
7.834
13.556
9.940
1.00
34.10
C
ATOM
2222
CB
PRO
D
94
7.201
14.957
9.670
1.00
32.63
C
ATOM
2223
CG
PRO
D
94
7.882
15.485
8.457
1.00
37.71
C
ATOM
2224
CD
PRO
D
94
8.380
14.248
7.607
1.00
35.59
C
ATOM
2225
C
PRO
D
94
6.729
12.581
10.396
1.00
33.49
C
ATOM
2226
O
PRO
D
94
6.261
11.740
9.592
1.00
32.95
O
ATOM
2227
N
GLU
D
95
6.306
12.700
11.664
1.00
31.40
N
ATOM
2228
CA
GLU
D
95
5.262
11.838
12.153
1.00
30.11
C
ATOM
2229
CB
GLU
D
95
5.248
11.771
13.704
1.00
31.59
C
ATOM
2230
CG
GLU
D
95
4.077
10.906
14.222
1.00
31.29
C
ATOM
2231
CD
GLU
D
95
4.067
10.647
15.747
1.00
35.15
C
ATOM
2232
OE1
GLU
D
95
3.312
9.736
16.195
1.00
42.96
O
ATOM
2233
OE2
GLU
D
95
4.774
11.367
16.469
1.00
42.80
O
ATOM
2234
C
GLU
D
95
3.932
12.424
11.620
1.00
27.97
C
ATOM
2235
O
GLU
D
95
3.754
13.630
11.549
1.00
26.66
O
ATOM
2236
N
CYS
D
96
3.012
11.552
11.271
1.00
27.21
N
ATOM
2237
CA
CYS
D
96
1.677
11.980
10.816
1.00
26.91
C
ATOM
2238
CB
CYS
D
96
0.972
10.808
10.196
1.00
25.79
C
ATOM
2239
SG
CYS
D
96
−0.756
11.121
9.525
1.00
25.47
S
ATOM
2240
C
CYS
D
96
0.833
12.538
11.964
1.00
27.38
C
ATOM
2241
O
CYS
D
96
0.514
11.837
12.909
1.00
27.92
O
ATOM
2242
N
TYR
D
97
0.452
13.801
11.856
1.00
27.76
N
ATOM
2243
CA
TYR
D
97
−0.365
14.433
12.897
1.00
27.92
C
ATOM
2244
CB
TYR
D
97
−0.652
15.878
12.528
1.00
28.47
C
ATOM
2245
CG
TYR
D
97
−1.354
16.646
13.643
1.00
29.52
C
ATOM
2246
CD1
TYR
D
97
−0.612
17.386
14.560
1.00
30.25
C
ATOM
2247
CE1
TYR
D
97
−1.252
18.093
15.628
1.00
32.82
C
ATOM
2248
CZ
TYR
D
97
−2.655
18.015
15.752
1.00
30.54
C
ATOM
2249
OH
TYR
D
97
−3.281
18.703
16.791
1.00
30.45
O
ATOM
2250
CE2
TYR
D
97
−3.416
17.260
14.837
1.00
29.38
C
ATOM
2251
CD2
TYR
D
97
−2.766
16.571
13.800
1.00
29.06
C
ATOM
2252
C
TYR
D
97
−1.658
13.672
13.141
1.00
28.09
C
ATOM
2253
O
TYR
D
97
−2.045
13.435
14.298
1.00
27.25
O
ATOM
2254
N
PHE
D
98
−2.318
13.251
12.054
1.00
28.03
N
ATOM
2255
CA
PHE
D
98
−3.631
12.613
12.195
1.00
26.18
C
ATOM
2256
CB
PHE
D
98
−4.407
12.608
10.863
1.00
27.78
C
ATOM
2257
CG
PHE
D
98
−4.754
14.003
10.412
1.00
25.25
C
ATOM
2258
CD1
PHE
D
98
−5.815
14.669
10.990
1.00
25.95
C
ATOM
2259
CE1
PHE
D
98
−6.092
15.991
10.625
1.00
25.50
C
ATOM
2260
CZ
PHE
D
98
−5.302
16.649
9.701
1.00
28.69
C
ATOM
2261
CE2
PHE
D
98
−4.223
16.002
9.144
1.00
31.29
C
ATOM
2262
CD2
PHE
D
98
−3.963
14.666
9.492
1.00
27.25
C
ATOM
2263
C
PHE
D
98
−3.515
11.238
12.812
1.00
28.26
C
ATOM
2264
O
PHE
D
98
−4.313
10.893
13.689
1.00
26.63
O
ATOM
2265
N
TYR
D
99
−2.538
10.431
12.375
1.00
28.21
N
ATOM
2266
CA
TYR
D
99
−2.406
9.132
13.024
1.00
30.03
C
ATOM
2267
CB
TYR
D
99
−1.371
8.282
12.328
1.00
29.69
C
ATOM
2268
CG
TYR
D
99
−1.522
6.820
12.659
1.00
31.63
C
ATOM
2269
CD1
TYR
D
99
−2.409
6.015
11.954
1.00
31.51
C
ATOM
2270
CE1
TYR
D
99
−2.547
4.671
12.258
1.00
31.48
C
ATOM
2271
CZ
TYR
D
99
−1.802
4.118
13.295
1.00
34.31
C
ATOM
2272
OH
TYR
D
99
−1.944
2.761
13.594
1.00
35.60
O
ATOM
2273
CE2
TYR
D
99
−0.911
4.897
14.014
1.00
34.34
C
ATOM
2274
CD2
TYR
D
99
−0.772
6.239
13.706
1.00
33.06
C
ATOM
2275
C
TYR
D
99
−2.050
9.285
14.524
1.00
30.74
C
ATOM
2276
O
TYR
D
99
−2.528
8.521
15.362
1.00
31.10
O
ATOM
2277
N
SER
D
100
−1.252
10.292
14.843
1.00
31.22
N
ATOM
2278
CA
SER
D
100
−0.808
10.499
16.231
1.00
33.97
C
ATOM
2279
CB
SER
D
100
0.374
11.452
16.281
1.00
33.74
C
ATOM
2280
OG
SER
D
100
0.531
11.965
17.613
1.00
40.80
O
ATOM
2281
C
SER
D
100
−1.937
11.009
17.142
1.00
33.35
C
ATOM
2282
O
SER
D
100
−2.116
10.476
18.259
1.00
34.24
O
ATOM
2283
N
LYS
D
101
−2.669
12.036
16.694
1.00
32.17
N
ATOM
2284
CA
LYS
D
101
−3.748
12.598
17.513
1.00
32.18
C
ATOM
2285
CB
LYS
D
101
−4.019
14.090
17.233
1.00
31.57
C
ATOM
2286
CG
LYS
D
101
−2.787
14.947
17.229
1.00
35.32
C
ATOM
2287
CD
LYS
D
101
−2.122
15.074
18.568
1.00
41.14
C
ATOM
2288
CE
LYS
D
101
−0.778
15.787
18.385
1.00
45.47
C
ATOM
2289
NZ
LYS
D
101
0.071
15.692
19.614
1.00
49.42
N
ATOM
2290
C
LYS
D
101
−5.043
11.822
17.475
1.00
32.87
C
ATOM
2291
O
LYS
D
101
−5.813
11.880
18.448
1.00
32.25
O
ATOM
2292
N
PHE
D
102
−5.303
11.104
16.366
1.00
32.74
N
ATOM
2293
CA
PHE
D
102
−6.603
10.506
16.130
1.00
31.60
C
ATOM
2294
CB
PHE
D
102
−7.279
11.089
14.871
1.00
31.91
C
ATOM
2295
CG
PHE
D
102
−7.714
12.529
15.022
1.00
29.94
C
ATOM
2296
CD1
PHE
D
102
−9.004
12.848
15.414
1.00
29.78
C
ATOM
2297
CE1
PHE
D
102
−9.402
14.211
15.537
1.00
24.97
C
ATOM
2298
CZ
PHE
D
102
−8.488
15.235
15.305
1.00
30.76
C
ATOM
2299
CE2
PHE
D
102
−7.204
14.894
14.901
1.00
31.66
C
ATOM
2300
CD2
PHE
D
102
−6.840
13.566
14.763
1.00
29.03
C
ATOM
2301
C
PHE
D
102
−6.491
9.005
16.040
1.00
32.14
C
ATOM
2302
O
PHE
D
102
−7.504
8.304
16.084
1.00
32.25
O
ATOM
2303
N
GLY
D
103
−5.275
8.480
15.911
1.00
31.31
N
ATOM
2304
CA
GLY
D
103
−5.174
7.038
15.785
1.00
31.79
C
ATOM
2305
C
GLY
D
103
−5.567
6.419
14.444
1.00
31.97
C
ATOM
2306
O
GLY
D
103
−5.626
5.206
14.333
1.00
32.46
O
ATOM
2307
N
GLU
D
104
−5.772
7.254
13.424
1.00
31.27
N
ATOM
2308
CA
GLU
D
104
−6.165
6.798
12.103
1.00
32.35
C
ATOM
2309
CB
GLU
D
104
−7.700
6.597
12.055
1.00
31.98
C
ATOM
2310
CG
GLU
D
104
−8.414
7.801
12.597
1.00
37.23
C
ATOM
2311
CD
GLU
D
104
−9.943
7.678
12.652
1.00
39.72
C
ATOM
2312
OE1
GLU
D
104
−10.592
8.690
13.160
1.00
49.09
O
ATOM
2313
OE2
GLU
D
104
−10.461
6.616
12.183
1.00
47.00
O
ATOM
2314
C
GLU
D
104
−5.777
7.887
11.094
1.00
28.30
C
ATOM
2315
O
GLU
D
104
−5.610
9.058
11.457
1.00
27.32
O
ATOM
2316
N
CYS
D
105
−5.711
7.505
9.823
1.00
26.03
N
ATOM
2317
CA
CYS
D
105
−5.317
8.438
8.770
1.00
24.64
C
ATOM
2318
CB
CYS
D
105
−3.794
8.380
8.639
1.00
24.89
C
ATOM
2319
SG
CYS
D
105
−3.126
9.266
7.198
1.00
24.05
S
ATOM
2320
C
CYS
D
105
−5.989
7.928
7.501
1.00
25.33
C
ATOM
2321
O
CYS
D
105
−6.010
6.721
7.249
1.00
24.40
O
ATOM
2322
N
SER
D
106
−6.619
8.836
6.741
1.00
25.56
N
ATOM
2323
CA
SER
D
106
−7.389
8.422
5.548
1.00
26.47
C
ATOM
2324
CB
SER
D
106
−8.516
9.453
5.249
1.00
26.24
C
ATOM
2325
OG
SER
D
106
−9.360
9.627
6.387
1.00
28.23
O
ATOM
2326
C
SER
D
106
−6.556
8.272
4.293
1.00
25.71
C
ATOM
2327
O
SER
D
106
−7.097
7.880
3.284
1.00
25.71
O
ATOM
2328
N
ASN
D
107
−5.249
8.580
4.324
1.00
26.46
N
ATOM
2329
CA
ASN
D
107
−4.446
8.453
3.098
1.00
25.74
C
ATOM
2330
CB
ASN
D
107
−3.369
9.531
3.066
1.00
26.14
C
ATOM
2331
CG
ASN
D
107
−2.628
9.608
1.732
1.00
26.49
C
ATOM
2332
OD1
ASN
D
107
−2.882
8.825
0.829
1.00
26.10
O
ATOM
2333
ND2
ASN
D
107
−1.747
10.610
1.599
1.00
25.07
N
ATOM
2334
C
ASN
D
107
−3.799
7.076
2.986
1.00
26.04
C
ATOM
2335
O
ASN
D
107
−2.829
6.795
3.679
1.00
24.98
O
ATOM
2336
N
LYS
D
108
−4.287
6.235
2.078
1.00
26.11
N
ATOM
2337
CA
LYS
D
108
−3.702
4.897
1.874
1.00
27.13
C
ATOM
2338
CB
LYS
D
108
−4.374
4.196
0.702
1.00
27.98
C
ATOM
2339
CG
LYS
D
108
−5.821
3.823
0.946
1.00
28.66
C
ATOM
2340
CD
LYS
D
108
−6.383
2.992
−0.222
1.00
28.13
C
ATOM
2341
CE
LYS
D
108
−7.909
3.041
−0.137
1.00
29.83
C
ATOM
2342
NZ
LYS
D
108
−8.548
2.711
−1.468
1.00
33.21
N
ATOM
2343
C
LYS
D
108
−2.236
5.019
1.559
1.00
28.60
C
ATOM
2344
O
LYS
D
108
−1.474
4.091
1.797
1.00
28.74
O
ATOM
2345
N
GLU
D
109
−1.833
6.181
1.040
1.00
28.07
N
ATOM
2346
CA
GLU
D
109
−0.454
6.365
0.587
1.00
29.49
C
ATOM
2347
CB
GLU
D
109
−0.418
6.922
−0.872
1.00
29.49
C
ATOM
2348
CG
GLU
D
109
−0.531
5.937
−2.016
1.00
33.84
C
ATOM
2349
CD
GLU
D
109
−1.877
5.272
−2.118
1.00
38.05
C
ATOM
2350
OE1
GLU
D
109
−2.892
5.951
−2.409
1.00
37.86
O
ATOM
2351
OE2
GLU
D
109
−1.903
4.025
−1.918
1.00
43.82
O
ATOM
2352
C
GLU
D
109
0.234
7.360
1.531
1.00
27.85
C
ATOM
2353
O
GLU
D
109
1.170
8.038
1.126
1.00
27.90
O
ATOM
2354
N
CYS
D
110
−0.224
7.468
2.794
1.00
27.24
N
ATOM
2355
CA
CYS
D
110
0.349
8.464
3.668
1.00
26.45
C
ATOM
2356
CB
CYS
D
110
−0.217
8.424
5.110
1.00
26.19
C
ATOM
2357
SG
CYS
D
110
0.473
9.819
6.015
1.00
26.60
S
ATOM
2358
C
CYS
D
110
1.861
8.236
3.757
1.00
26.83
C
ATOM
2359
O
CYS
D
110
2.306
7.136
4.093
1.00
27.21
O
ATOM
2360
N
PRO
D
111
2.644
9.264
3.464
1.00
28.24
N
ATOM
2361
CA
PRO
D
111
4.100
9.026
3.588
1.00
29.52
C
ATOM
2362
CB
PRO
D
111
4.693
9.997
2.571
1.00
29.24
C
ATOM
2363
CG
PRO
D
111
3.697
11.231
2.593
1.00
29.52
C
ATOM
2364
CD
PRO
D
111
2.314
10.617
2.940
1.00
28.03
C
ATOM
2365
C
PRO
D
111
4.652
9.291
5.006
1.00
30.98
C
ATOM
2366
O
PRO
D
111
5.844
9.085
5.254
1.00
30.98
O
ATOM
2367
N
PHE
D
112
3.804
9.736
5.928
1.00
30.89
N
ATOM
2368
CA
PHE
D
112
4.269
10.140
7.250
1.00
31.40
C
ATOM
2369
CB
PHE
D
112
3.488
11.400
7.720
1.00
30.20
C
ATOM
2370
CG
PHE
D
112
3.666
12.592
6.808
1.00
31.21
C
ATOM
2371
CD1
PHE
D
112
4.830
13.347
6.840
1.00
29.10
C
ATOM
2372
CE1
PHE
D
112
4.997
14.422
5.991
1.00
29.55
C
ATOM
2373
CZ
PHE
D
112
3.956
14.776
5.080
1.00
30.53
C
ATOM
2374
CE2
PHE
D
112
2.787
14.019
5.060
1.00
29.65
C
ATOM
2375
CD2
PHE
D
112
2.657
12.959
5.902
1.00
29.41
C
ATOM
2376
C
PHE
D
112
4.207
8.961
8.248
1.00
32.22
C
ATOM
2377
O
PHE
D
112
3.457
7.988
8.060
1.00
31.82
O
ATOM
2378
N
LEU
D
113
5.006
9.029
9.317
1.00
32.63
N
ATOM
2379
CA
LEU
D
113
5.022
7.932
10.298
1.00
33.39
C
ATOM
2380
CB
LEU
D
113
6.094
8.155
11.371
1.00
33.96
C
ATOM
2381
CG
LEU
D
113
7.531
8.394
10.944
1.00
36.30
C
ATOM
2382
CD1
LEU
D
113
8.354
8.768
12.166
1.00
38.73
C
ATOM
2383
CD2
LEU
D
113
8.092
7.138
10.288
1.00
40.51
C
ATOM
2384
C
LEU
D
113
3.682
7.730
11.012
1.00
33.17
C
ATOM
2385
O
LEU
D
113
3.125
8.664
11.575
1.00
32.95
O
ATOM
2386
N
HIS
D
114
3.226
6.489
11.016
1.00
33.23
N
ATOM
2387
CA
HIS
D
114
2.100
6.069
11.799
1.00
35.48
C
ATOM
2388
CB
HIS
D
114
1.117
5.267
10.947
1.00
34.35
C
ATOM
2389
CG
HIS
D
114
0.415
6.058
9.871
1.00
30.91
C
ATOM
2390
ND1
HIS
D
114
−0.475
5.460
9.007
1.00
30.62
N
ATOM
2391
CE1
HIS
D
114
−0.961
6.359
8.166
1.00
29.38
C
ATOM
2392
NE2
HIS
D
114
−0.466
7.543
8.486
1.00
21.78
N
ATOM
2393
CD2
HIS
D
114
0.420
7.374
9.546
1.00
25.39
C
ATOM
2394
C
HIS
D
114
2.577
5.228
13.001
1.00
37.49
C
ATOM
2395
O
HIS
D
114
2.769
4.011
12.893
1.00
38.30
O
ATOM
2396
N
ILE
D
115
2.744
5.897
14.124
1.00
40.28
N
ATOM
2397
CA
ILE
D
115
3.278
5.292
15.358
1.00
44.28
C
ATOM
2398
CB
ILE
D
115
4.306
6.217
16.026
1.00
43.85
C
ATOM
2399
CG1
ILE
D
115
5.492
6.454
15.092
1.00
43.41
C
ATOM
2400
CD1
ILE
D
115
6.188
7.704
15.411
1.00
43.55
C
ATOM
2401
CG2
ILE
D
115
4.798
5.626
17.367
1.00
45.91
C
ATOM
2402
C
ILE
D
115
2.145
5.013
16.347
1.00
46.74
C
ATOM
2403
O
ILE
D
115
1.410
5.930
16.739
1.00
45.72
O
ATOM
2404
N
ASP
D
116
2.009
3.739
16.714
1.00
50.52
N
ATOM
2405
CA
ASP
D
116
0.967
3.299
17.636
1.00
54.53
C
ATOM
2406
CB
ASP
D
116
0.748
1.815
17.497
1.00
54.79
C
ATOM
2407
CG
ASP
D
116
−0.004
1.487
16.252
1.00
57.65
C
ATOM
2408
OD1
ASP
D
116
−0.920
2.284
15.908
1.00
58.31
O
ATOM
2409
OD2
ASP
D
116
0.332
0.459
15.605
1.00
60.82
O
ATOM
2410
C
ASP
D
116
1.257
3.653
19.082
1.00
57.26
C
ATOM
2411
O
ASP
D
116
2.430
3.687
19.507
1.00
57.07
O
ATOM
2412
N
PRO
D
117
0.187
3.944
19.844
1.00
59.98
N
ATOM
2413
CA
PRO
D
117
0.354
4.429
21.206
1.00
62.24
C
ATOM
2414
CB
PRO
D
117
−1.063
4.434
21.747
1.00
62.12
C
ATOM
2415
CG
PRO
D
117
−1.913
4.600
20.533
1.00
61.61
C
ATOM
2416
CD
PRO
D
117
−1.233
3.827
19.468
1.00
60.37
C
ATOM
2417
C
PRO
D
117
1.253
3.461
21.965
1.00
64.67
C
ATOM
2418
O
PRO
D
117
1.000
2.237
21.993
1.00
64.83
O
ATOM
2419
N
GLU
D
118
2.326
4.029
22.514
1.00
67.27
N
ATOM
2420
CA
GLU
D
118
3.477
3.280
23.006
1.00
69.59
C
ATOM
2421
CB
GLU
D
118
4.684
4.230
23.201
1.00
70.33
C
ATOM
2422
CG
GLU
D
118
5.298
4.836
21.899
1.00
73.39
C
ATOM
2423
CD
GLU
D
118
4.568
6.103
21.334
1.00
76.34
C
ATOM
2424
OE1
GLU
D
118
5.246
7.142
21.133
1.00
78.16
O
ATOM
2425
OE2
GLU
D
118
3.342
6.068
21.065
1.00
76.31
O
ATOM
2426
C
GLU
D
118
3.091
2.594
24.317
1.00
70.03
C
ATOM
2427
O
GLU
D
118
2.772
1.396
24.331
1.00
70.42
O
ATOM
2428
OXT
GLU
D
118
3.057
3.230
25.381
1.00
70.37
O
ATOM
2429
ZN
ZN
D
502
−0.941
9.474
7.886
1.00
26.96
ZN
ATOM
2430
ZN
ZN
D
501
12.470
23.684
4.582
1.00
38.67
ZN
ATOM
2431
N
HIS
E
58
−45.599
5.932
−6.806
1.00
42.25
N
ATOM
2432
CA
HIS
E
58
−44.990
6.748
−5.741
1.00
41.89
C
ATOM
2433
CB
HIS
E
58
−43.463
6.785
−5.831
1.00
44.50
C
ATOM
2434
CG
HIS
E
58
−42.795
6.886
−4.479
1.00
50.77
C
ATOM
2435
ND1
HIS
E
58
−43.456
7.346
−3.347
1.00
54.95
N
ATOM
2436
CE1
HIS
E
58
−42.629
7.341
−2.319
1.00
56.42
C
ATOM
2437
NE2
HIS
E
58
−41.448
6.908
−2.737
1.00
57.08
N
ATOM
2438
CD2
HIS
E
58
−41.527
6.607
−4.081
1.00
54.69
C
ATOM
2439
C
HIS
E
58
−45.544
8.155
−5.678
1.00
39.42
C
ATOM
2440
O
HIS
E
58
−46.314
8.545
−6.529
1.00
39.21
O
ATOM
2441
N
HIS
E
59
−45.137
8.891
−4.639
1.00
36.77
N
ATOM
2442
CA
HIS
E
59
−45.638
10.226
−4.323
1.00
34.79
C
ATOM
2443
CB
HIS
E
59
−45.422
10.533
−2.828
1.00
34.59
C
ATOM
2444
CG
HIS
E
59
−46.395
9.818
−1.940
1.00
33.03
C
ATOM
2445
ND1
HIS
E
59
−47.619
10.358
−1.596
1.00
32.36
N
ATOM
2446
CE1
HIS
E
59
−48.284
9.494
−0.853
1.00
31.07
C
ATOM
2447
NE2
HIS
E
59
−47.546
8.412
−0.712
1.00
33.32
N
ATOM
2448
CD2
HIS
E
59
−46.366
8.577
−1.404
1.00
33.19
C
ATOM
2449
C
HIS
E
59
−45.044
11.294
−5.192
1.00
33.88
C
ATOM
2450
O
HIS
E
59
−45.621
12.347
−5.359
1.00
34.21
O
ATOM
2451
N
MET
E
60
−43.868
11.030
−5.751
1.00
33.64
N
ATOM
2452
CA
MET
E
60
−43.150
12.064
−6.456
1.00
32.83
C
ATOM
2453
CB
MET
E
60
−41.660
12.062
−6.014
1.00
33.04
C
ATOM
2454
CG
MET
E
60
−41.453
12.437
−4.513
1.00
31.91
C
ATOM
2455
SD
MET
E
60
−41.776
14.194
−4.217
1.00
32.73
S
ATOM
2456
CE
MET
E
60
−40.473
15.014
−5.195
1.00
37.28
C
ATOM
2457
C
MET
E
60
−43.287
11.794
−7.946
1.00
32.82
C
ATOM
2458
O
MET
E
60
−43.281
10.640
−8.378
1.00
31.69
O
ATOM
2459
N
SER
E
61
−43.409
12.856
−8.720
1.00
34.88
N
ATOM
2460
CA
SER
E
61
−43.525
12.717
−10.180
1.00
36.77
C
ATOM
2461
CB
SER
E
61
−43.851
14.048
−10.771
1.00
36.98
C
ATOM
2462
OG
SER
E
61
−42.777
14.923
−10.515
1.00
36.64
O
ATOM
2463
C
SER
E
61
−42.240
12.186
−10.826
1.00
38.65
C
ATOM
2464
O
SER
E
61
−42.276
11.508
−11.861
1.00
38.84
O
ATOM
2465
N
GLY
E
62
−41.109
12.548
−10.238
1.00
38.90
N
ATOM
2466
CA
GLY
E
62
−39.821
11.937
−10.565
1.00
42.02
C
ATOM
2467
C
GLY
E
62
−38.915
12.104
−9.370
1.00
42.64
C
ATOM
2468
O
GLY
E
62
−39.227
12.872
−8.468
1.00
42.24
O
ATOM
2469
N
GLU
E
63
−37.796
11.393
−9.347
1.00
45.02
N
ATOM
2470
CA
GLU
E
63
−36.847
11.545
−8.225
1.00
47.21
C
ATOM
2471
CB
GLU
E
63
−36.811
10.301
−7.315
1.00
47.94
C
ATOM
2472
CG
GLU
E
63
−36.103
9.079
−7.946
1.00
50.89
C
ATOM
2473
CD
GLU
E
63
−35.983
7.892
−7.000
1.00
52.10
C
ATOM
2474
OE1
GLU
E
63
−36.013
8.100
−5.750
1.00
59.78
O
ATOM
2475
OE2
GLU
E
63
−35.856
6.753
−7.508
1.00
58.02
O
ATOM
2476
C
GLU
E
63
−35.450
11.851
−8.749
1.00
46.14
C
ATOM
2477
O
GLU
E
63
−35.088
11.464
−9.878
1.00
46.17
O
ATOM
2478
N
LYS
E
64
−34.683
12.571
−7.939
1.00
44.27
N
ATOM
2479
CA
LYS
E
64
−33.270
12.750
−8.212
1.00
42.93
C
ATOM
2480
CB
LYS
E
64
−32.739
13.869
−7.367
1.00
41.82
C
ATOM
2481
CG
LYS
E
64
−33.343
15.218
−7.693
1.00
41.03
C
ATOM
2482
CD
LYS
E
64
−33.057
16.133
−6.512
1.00
41.77
C
ATOM
2483
CE
LYS
E
64
−33.368
17.576
−6.788
1.00
41.00
C
ATOM
2484
NZ
LYS
E
64
−32.771
18.415
−5.702
1.00
40.32
N
ATOM
2485
C
LYS
E
64
−32.560
11.436
−7.918
1.00
42.50
C
ATOM
2486
O
LYS
E
64
−33.026
10.610
−7.135
1.00
44.38
O
ATOM
2487
N
THR
E
65
−31.441
11.193
−8.562
1.00
42.38
N
ATOM
2488
CA
THR
E
65
−30.831
9.888
−8.402
1.00
41.77
C
ATOM
2489
CB
THR
E
65
−30.720
9.186
−9.760
1.00
42.28
C
ATOM
2490
OG1
THR
E
65
−30.159
10.128
−10.693
1.00
41.94
O
ATOM
2491
CG2
THR
E
65
−32.135
8.713
−10.241
1.00
45.27
C
ATOM
2492
C
THR
E
65
−29.423
9.995
−7.862
1.00
40.59
C
ATOM
2493
O
THR
E
65
−28.849
8.977
−7.475
1.00
40.78
O
ATOM
2494
N
VAL
E
66
−28.842
11.193
−7.905
1.00
38.83
N
ATOM
2495
CA
VAL
E
66
−27.426
11.331
−7.492
1.00
37.55
C
ATOM
2496
CB
VAL
E
66
−26.459
11.437
−8.729
1.00
38.38
C
ATOM
2497
CG1
VAL
E
66
−25.006
11.254
−8.300
1.00
37.81
C
ATOM
2498
CG2
VAL
E
66
−26.794
10.360
−9.780
1.00
38.40
C
ATOM
2499
C
VAL
E
66
−27.227
12.484
−6.511
1.00
35.67
C
ATOM
2500
O
VAL
E
66
−27.741
13.564
−6.731
1.00
35.07
O
ATOM
2501
N
VAL
E
67
−26.471
12.247
−5.427
1.00
35.49
N
ATOM
2502
CA
VAL
E
67
−26.180
13.321
−4.440
1.00
33.32
C
ATOM
2503
CB
VAL
E
67
−25.455
12.741
−3.186
1.00
34.57
C
ATOM
2504
CG1
VAL
E
67
−25.038
13.845
−2.204
1.00
32.91
C
ATOM
2505
CG2
VAL
E
67
−26.283
11.653
−2.507
1.00
34.32
C
ATOM
2506
C
VAL
E
67
−25.326
14.407
−5.084
1.00
33.24
C
ATOM
2507
O
VAL
E
67
−24.399
14.102
−5.828
1.00
33.82
O
ATOM
2508
N
CYS
E
68
−25.604
15.669
−4.811
1.00
31.69
N
ATOM
2509
CA
CYS
E
68
−24.799
16.744
−5.313
1.00
31.28
C
ATOM
2510
CB
CYS
E
68
−25.538
18.035
−5.075
1.00
29.96
C
ATOM
2511
SG
CYS
E
68
−24.739
19.465
−5.730
1.00
33.39
S
ATOM
2512
C
CYS
E
68
−23.381
16.862
−4.647
1.00
31.68
C
ATOM
2513
O
CYS
E
68
−23.271
17.214
−3.467
1.00
28.47
O
ATOM
2514
N
LYS
E
69
−22.325
16.598
−5.431
1.00
31.61
N
ATOM
2515
CA
LYS
E
69
−20.908
16.763
−5.017
1.00
32.83
C
ATOM
2516
CB
LYS
E
69
−20.027
16.837
−6.279
1.00
33.94
C
ATOM
2517
CG
LYS
E
69
−19.380
15.596
−6.682
1.00
36.27
C
ATOM
2518
CD
LYS
E
69
−18.340
15.955
−7.751
1.00
36.61
C
ATOM
2519
CE
LYS
E
69
−16.997
16.551
−7.151
1.00
35.02
C
ATOM
2520
NZ
LYS
E
69
−16.668
17.768
−7.999
1.00
34.32
N
ATOM
2521
C
LYS
E
69
−20.618
18.068
−4.349
1.00
32.43
C
ATOM
2522
O
LYS
E
69
−19.978
18.119
−3.327
1.00
33.76
O
ATOM
2523
N
HIS
E
70
−20.993
19.132
−5.029
1.00
32.65
N
ATOM
2524
CA
HIS
E
70
−20.764
20.507
−4.616
1.00
34.13
C
ATOM
2525
CB
HIS
E
70
−21.208
21.475
−5.716
1.00
35.61
C
ATOM
2526
CG
HIS
E
70
−20.401
21.362
−6.974
1.00
41.83
C
ATOM
2527
ND1
HIS
E
70
−20.975
21.215
−8.219
1.00
44.87
N
ATOM
2528
CE1
HIS
E
70
−20.021
21.107
−9.131
1.00
46.74
C
ATOM
2529
NE2
HIS
E
70
−18.850
21.169
−8.521
1.00
46.66
N
ATOM
2530
CD2
HIS
E
70
−19.057
21.348
−7.173
1.00
45.07
C
ATOM
2531
C
HIS
E
70
−21.499
20.875
−3.375
1.00
33.85
C
ATOM
2532
O
HIS
E
70
−20.965
21.612
−2.540
1.00
32.81
O
ATOM
2533
N
TRP
E
71
−22.735
20.382
−3.234
1.00
32.72
N
ATOM
2534
CA
TRP
E
71
−23.473
20.633
−1.999
1.00
31.55
C
ATOM
2535
CB
TRP
E
71
−24.898
20.093
−2.128
1.00
31.78
C
ATOM
2536
CG
TRP
E
71
−25.618
20.081
−0.863
1.00
30.88
C
ATOM
2537
CD1
TRP
E
71
−26.208
21.145
−0.255
1.00
32.24
C
ATOM
2538
NE1
TRP
E
71
−26.752
20.766
0.939
1.00
30.42
N
ATOM
2539
CE2
TRP
E
71
−26.545
19.423
1.119
1.00
31.60
C
ATOM
2540
CD2
TRP
E
71
−25.810
18.959
0.001
1.00
31.97
C
ATOM
2541
CE3
TRP
E
71
−25.453
17.599
−0.064
1.00
29.83
C
ATOM
2542
CZ3
TRP
E
71
−25.828
16.755
0.982
1.00
31.73
C
ATOM
2543
CH2
TRP
E
71
−26.576
17.246
2.082
1.00
31.68
C
ATOM
2544
CZ2
TRP
E
71
−26.932
18.579
2.164
1.00
33.50
C
ATOM
2545
C
TRP
E
71
−22.779
19.988
−0.793
1.00
31.55
C
ATOM
2546
O
TRP
E
71
−22.696
20.588
0.273
1.00
31.49
O
ATOM
2547
N
LEU
E
72
−22.324
18.753
−0.940
1.00
31.49
N
ATOM
2548
CA
LEU
E
72
−21.521
18.104
0.095
1.00
33.29
C
ATOM
2549
CB
LEU
E
72
−20.882
16.817
−0.408
1.00
32.05
C
ATOM
2550
CG
LEU
E
72
−21.709
15.628
−0.834
1.00
33.40
C
ATOM
2551
CD1
LEU
E
72
−20.740
14.576
−1.311
1.00
33.05
C
ATOM
2552
CD2
LEU
E
72
−22.533
15.074
0.324
1.00
34.38
C
ATOM
2553
C
LEU
E
72
−20.421
18.995
0.666
1.00
35.07
C
ATOM
2554
O
LEU
E
72
−20.179
18.977
1.889
1.00
34.12
O
ATOM
2555
N
ARG
E
73
−19.811
19.800
−0.211
1.00
36.81
N
ATOM
2556
CA
ARG
E
73
−18.657
20.617
0.109
1.00
40.54
C
ATOM
2557
CB
ARG
E
73
−17.582
20.487
−0.995
1.00
40.08
C
ATOM
2558
CG
ARG
E
73
−17.188
19.023
−1.253
1.00
38.53
C
ATOM
2559
CD
ARG
E
73
−15.766
18.806
−1.829
1.00
42.91
C
ATOM
2560
NE
ARG
E
73
−14.721
19.373
−0.957
1.00
44.71
N
ATOM
2561
CZ
ARG
E
73
−13.988
20.441
−1.248
1.00
41.53
C
ATOM
2562
NH1
ARG
E
73
−14.110
21.056
−2.418
1.00
38.99
N
ATOM
2563
NH2
ARG
E
73
−13.095
20.874
−0.366
1.00
39.88
N
ATOM
2564
C
ARG
E
73
−19.038
22.074
0.384
1.00
42.77
C
ATOM
2565
O
ARG
E
73
−18.175
22.881
0.710
1.00
44.16
O
ATOM
2566
N
GLY
E
74
−20.336
22.386
0.298
1.00
44.23
N
ATOM
2567
CA
GLY
E
74
−20.858
23.741
0.583
1.00
46.05
C
ATOM
2568
C
GLY
E
74
−20.728
24.678
−0.610
1.00
46.86
C
ATOM
2569
O
GLY
E
74
−20.793
25.910
−0.460
1.00
48.02
O
ATOM
2570
N
LEU
E
75
−20.532
24.104
−1.791
1.00
47.48
N
ATOM
2571
CA
LEU
E
75
−20.302
24.871
−3.020
1.00
48.84
C
ATOM
2572
CB
LEU
E
75
−19.129
24.266
−3.816
1.00
49.51
C
ATOM
2573
CG
LEU
E
75
−17.738
24.086
−3.189
1.00
50.58
C
ATOM
2574
CD1
LEU
E
75
−16.902
23.169
−4.073
1.00
50.57
C
ATOM
2575
CD2
LEU
E
75
−17.066
25.434
−2.994
1.00
50.81
C
ATOM
2576
C
LEU
E
75
−21.498
24.943
−3.983
1.00
49.52
C
ATOM
2577
O
LEU
E
75
−21.321
25.345
−5.153
1.00
50.54
O
ATOM
2578
N
CYS
E
76
−22.682
24.497
−3.561
1.00
48.50
N
ATOM
2579
CA
CYS
E
76
−23.841
24.558
−4.460
1.00
49.32
C
ATOM
2580
CB
CYS
E
76
−24.746
23.332
−4.338
1.00
49.22
C
ATOM
2581
SG
CYS
E
76
−25.966
23.095
−5.719
1.00
45.68
S
ATOM
2582
C
CYS
E
76
−24.616
25.803
−4.123
1.00
50.25
C
ATOM
2583
O
CYS
E
76
−24.951
26.040
−2.956
1.00
50.15
O
ATOM
2584
N
LYS
E
77
−24.885
26.608
−5.145
1.00
51.41
N
ATOM
2585
CA
LYS
E
77
−25.629
27.849
−4.945
1.00
52.98
C
ATOM
2586
CB
LYS
E
77
−24.868
29.022
−5.590
1.00
54.17
C
ATOM
2587
CG
LYS
E
77
−23.520
29.356
−4.910
1.00
55.63
C
ATOM
2588
CD
LYS
E
77
−23.643
29.529
−3.369
1.00
59.35
C
ATOM
2589
CE
LYS
E
77
−22.265
29.528
−2.689
1.00
60.06
C
ATOM
2590
NZ
LYS
E
77
−22.296
28.836
−1.352
1.00
63.41
N
ATOM
2591
C
LYS
E
77
−27.092
27.775
−5.458
1.00
52.74
C
ATOM
2592
O
LYS
E
77
−27.834
28.756
−5.373
1.00
53.10
O
ATOM
2593
N
LYS
E
78
−27.478
26.606
−5.971
1.00
52.29
N
ATOM
2594
CA
LYS
E
78
−28.781
26.376
−6.618
1.00
51.59
C
ATOM
2595
CB
LYS
E
78
−28.629
25.314
−7.701
1.00
51.61
C
ATOM
2596
CG
LYS
E
78
−27.597
25.644
−8.736
1.00
55.37
C
ATOM
2597
CD
LYS
E
78
−27.595
24.600
−9.828
1.00
60.45
C
ATOM
2598
CE
LYS
E
78
−26.265
24.629
−10.576
1.00
64.73
C
ATOM
2599
NZ
LYS
E
78
−26.241
23.689
−11.766
1.00
67.80
N
ATOM
2600
C
LYS
E
78
−29.925
25.946
−5.695
1.00
50.45
C
ATOM
2601
O
LYS
E
78
−31.070
25.859
−6.152
1.00
50.69
O
ATOM
2602
N
GLY
E
79
−29.622
25.633
−4.431
1.00
48.61
N
ATOM
2603
CA
GLY
E
79
−30.626
25.169
−3.467
1.00
46.20
C
ATOM
2604
C
GLY
E
79
−31.582
24.117
−4.026
1.00
45.27
C
ATOM
2605
O
GLY
E
79
−31.149
23.109
−4.600
1.00
42.86
O
ATOM
2606
N
ASP
E
80
−32.889
24.387
−3.878
1.00
45.12
N
ATOM
2607
CA
ASP
E
80
−33.971
23.474
−4.336
1.00
44.97
C
ATOM
2608
CB
ASP
E
80
−35.331
23.877
−3.733
1.00
45.06
C
ATOM
2609
CG
ASP
E
80
−35.385
23.621
−2.241
1.00
45.92
C
ATOM
2610
OD1
ASP
E
80
−34.552
22.805
−1.797
1.00
50.22
O
ATOM
2611
OD2
ASP
E
80
−36.209
24.215
−1.505
1.00
43.28
O
ATOM
2612
C
ASP
E
80
−34.055
23.260
−5.850
1.00
45.13
C
ATOM
2613
O
ASP
E
80
−34.584
22.247
−6.298
1.00
44.46
O
ATOM
2614
N
GLN
E
81
−33.486
24.186
−6.620
1.00
45.80
N
ATOM
2615
CA
GLN
E
81
−33.488
24.107
−8.089
1.00
46.94
C
ATOM
2616
CB
GLN
E
81
−33.388
25.513
−8.722
1.00
47.91
C
ATOM
2617
CG
GLN
E
81
−34.653
26.382
−8.648
1.00
49.80
C
ATOM
2618
CD
GLN
E
81
−35.031
26.756
−7.225
1.00
52.50
C
ATOM
2619
OE1
GLN
E
81
−34.201
27.259
−6.450
1.00
56.42
O
ATOM
2620
NE2
GLN
E
81
−36.271
26.508
−6.866
1.00
53.27
N
ATOM
2621
C
GLN
E
81
−32.354
23.226
−8.628
1.00
46.85
C
ATOM
2622
O
GLN
E
81
−32.232
23.038
−9.840
1.00
47.31
O
ATOM
2623
N
CYS
E
82
−31.532
22.660
−7.741
1.00
46.00
N
ATOM
2624
CA
CYS
E
82
−30.473
21.759
−8.197
1.00
44.71
C
ATOM
2625
CB
CYS
E
82
−29.479
21.471
−7.058
1.00
44.58
C
ATOM
2626
SG
CYS
E
82
−28.029
20.574
−7.678
1.00
44.34
S
ATOM
2627
C
CYS
E
82
−31.048
20.446
−8.726
1.00
44.24
C
ATOM
2628
O
CYS
E
82
−32.071
19.975
−8.225
1.00
44.60
O
ATOM
2629
N
GLU
E
83
−30.404
19.860
−9.739
1.00
43.02
N
ATOM
2630
CA
GLU
E
83
−30.808
18.571
−10.321
1.00
42.89
C
ATOM
2631
CB
GLU
E
83
−30.223
18.471
−11.729
1.00
43.36
C
ATOM
2632
CG
GLU
E
83
−29.088
19.514
−11.963
1.00
47.27
C
ATOM
2633
CD
GLU
E
83
−28.176
19.165
−13.153
1.00
48.75
C
ATOM
2634
OE1
GLU
E
83
−27.193
19.932
−13.395
1.00
55.39
O
ATOM
2635
OE2
GLU
E
83
−28.415
18.114
−13.830
1.00
55.23
O
ATOM
2636
C
GLU
E
83
−30.335
17.384
−9.494
1.00
39.93
C
ATOM
2637
O
GLU
E
83
−30.741
16.215
−9.687
1.00
39.21
O
ATOM
2638
N
PHE
E
84
−29.430
17.670
−8.570
1.00
37.89
N
ATOM
2639
CA
PHE
E
84
−28.891
16.613
−7.756
1.00
35.71
C
ATOM
2640
CB
PHE
E
84
−27.343
16.609
−7.806
1.00
35.62
C
ATOM
2641
CG
PHE
E
84
−26.766
16.461
−9.205
1.00
36.55
C
ATOM
2642
CD1
PHE
E
84
−26.238
17.561
−9.868
1.00
35.78
C
ATOM
2643
CE1
PHE
E
84
−25.683
17.440
−11.182
1.00
38.26
C
ATOM
2644
CZ
PHE
E
84
−25.649
16.207
−11.803
1.00
38.82
C
ATOM
2645
CE2
PHE
E
84
−26.161
15.078
−11.147
1.00
42.35
C
ATOM
2646
CD2
PHE
E
84
−26.716
15.210
−9.829
1.00
39.76
C
ATOM
2647
C
PHE
E
84
−29.455
16.778
−6.320
1.00
34.41
C
ATOM
2648
O
PHE
E
84
−29.864
17.860
−5.913
1.00
33.89
O
ATOM
2649
N
LEU
E
85
−29.455
15.676
−5.603
1.00
33.01
N
ATOM
2650
CA
LEU
E
85
−29.962
15.539
−4.242
1.00
34.42
C
ATOM
2651
CB
LEU
E
85
−29.888
14.039
−3.909
1.00
34.42
C
ATOM
2652
CG
LEU
E
85
−30.854
12.999
−3.361
1.00
38.28
C
ATOM
2653
CD1
LEU
E
85
−32.315
13.248
−3.771
1.00
39.00
C
ATOM
2654
CD2
LEU
E
85
−30.402
11.593
−3.836
1.00
34.69
C
ATOM
2655
C
LEU
E
85
−29.122
16.367
−3.237
1.00
34.30
C
ATOM
2656
O
LEU
E
85
−27.880
16.259
−3.198
1.00
33.65
O
ATOM
2657
N
HIS
E
86
−29.786
17.193
−2.434
1.00
33.63
N
ATOM
2658
CA
HIS
E
86
−29.142
17.847
−1.317
1.00
33.34
C
ATOM
2659
CB
HIS
E
86
−29.541
19.304
−1.260
1.00
32.70
C
ATOM
2660
CG
HIS
E
86
−28.884
20.172
−2.295
1.00
31.14
C
ATOM
2661
ND1
HIS
E
86
−28.827
21.541
−2.162
1.00
30.21
N
ATOM
2662
CE1
HIS
E
86
−28.204
22.066
−3.195
1.00
31.04
C
ATOM
2663
NE2
HIS
E
86
−27.817
21.077
−3.983
1.00
27.66
N
ATOM
2664
CD2
HIS
E
86
−28.236
19.883
−3.447
1.00
28.50
C
ATOM
2665
C
HIS
E
86
−29.508
17.096
−0.031
1.00
34.46
C
ATOM
2666
O
HIS
E
86
−30.227
17.602
0.834
1.00
34.31
O
ATOM
2667
N
GLU
E
87
−29.018
15.860
0.059
1.00
35.41
N
ATOM
2668
CA
GLU
E
87
−29.192
15.005
1.212
1.00
37.64
C
ATOM
2669
CB
GLU
E
87
−30.511
14.229
1.121
1.00
37.29
C
ATOM
2670
CG
GLU
E
87
−30.694
13.235
2.264
1.00
38.59
C
ATOM
2671
CD
GLU
E
87
−31.891
12.280
2.135
1.00
38.23
C
ATOM
2672
OE1
GLU
E
87
−32.573
12.259
1.077
1.00
35.85
O
ATOM
2673
OE2
GLU
E
87
−32.117
11.536
3.137
1.00
41.22
O
ATOM
2674
C
GLU
E
87
−28.040
13.999
1.175
1.00
39.03
C
ATOM
2675
O
GLU
E
87
−27.698
13.479
0.100
1.00
38.12
O
ATOM
2676
N
TYR
E
88
−27.453
13.683
2.329
1.00
40.99
N
ATOM
2677
CA
TYR
E
88
−26.438
12.647
2.306
1.00
43.56
C
ATOM
2678
CB
TYR
E
88
−25.405
12.692
3.460
1.00
44.72
C
ATOM
2679
CG
TYR
E
88
−24.238
11.718
3.169
1.00
47.61
C
ATOM
2680
CD1
TYR
E
88
−23.255
12.023
2.216
1.00
49.16
C
ATOM
2681
CE1
TYR
E
88
−22.220
11.110
1.913
1.00
48.23
C
ATOM
2682
CZ
TYR
E
88
−22.190
9.907
2.524
1.00
44.96
C
ATOM
2683
OH
TYR
E
88
−21.205
9.042
2.249
1.00
49.62
O
ATOM
2684
CE2
TYR
E
88
−23.132
9.561
3.470
1.00
49.06
C
ATOM
2685
CD2
TYR
E
88
−24.161
10.464
3.790
1.00
48.49
C
ATOM
2686
C
TYR
E
88
−27.123
11.341
2.243
1.00
44.32
C
ATOM
2687
O
TYR
E
88
−27.732
10.920
3.203
1.00
45.92
O
ATOM
2688
N
ASP
E
89
−27.039
10.698
1.093
1.00
45.86
N
ATOM
2689
CA
ASP
E
89
−27.430
9.313
0.980
1.00
47.31
C
ATOM
2690
CB
ASP
E
89
−28.644
9.171
0.048
1.00
46.75
C
ATOM
2691
CG
ASP
E
89
−29.146
7.733
−0.071
1.00
47.59
C
ATOM
2692
OD1
ASP
E
89
−28.410
6.765
0.237
1.00
46.06
O
ATOM
2693
OD2
ASP
E
89
−30.306
7.566
−0.503
1.00
50.29
O
ATOM
2694
C
ASP
E
89
−26.221
8.580
0.428
1.00
48.29
C
ATOM
2695
O
ASP
E
89
−25.901
8.717
−0.747
1.00
47.55
O
ATOM
2696
N
MET
E
90
−25.566
7.805
1.295
1.00
50.53
N
ATOM
2697
CA
MET
E
90
−24.346
7.060
0.956
1.00
53.26
C
ATOM
2698
CB
MET
E
90
−23.756
6.309
2.188
1.00
53.27
C
ATOM
2699
CG
MET
E
90
−24.552
5.053
2.647
1.00
56.70
C
ATOM
2700
SD
MET
E
90
−24.136
4.344
4.281
1.00
58.92
S
ATOM
2701
CE
MET
E
90
−22.763
3.255
3.864
1.00
60.49
C
ATOM
2702
C
MET
E
90
−24.551
6.100
−0.214
1.00
52.16
C
ATOM
2703
O
MET
E
90
−23.581
5.736
−0.879
1.00
52.83
O
ATOM
2704
N
THR
E
91
−25.810
5.715
−0.474
1.00
51.03
N
ATOM
2705
CA
THR
E
91
−26.135
4.762
−1.551
1.00
49.35
C
ATOM
2706
CB
THR
E
91
−27.402
3.887
−1.243
1.00
49.74
C
ATOM
2707
OG1
THR
E
91
−28.539
4.732
−1.018
1.00
49.46
O
ATOM
2708
CG2
THR
E
91
−27.172
3.001
−0.031
1.00
50.99
C
ATOM
2709
C
THR
E
91
−26.377
5.443
−2.873
1.00
47.57
C
ATOM
2710
O
THR
E
91
−26.556
4.765
−3.900
1.00
47.97
O
ATOM
2711
N
LYS
E
92
−26.410
6.773
−2.870
1.00
44.84
N
ATOM
2712
CA
LYS
E
92
−26.694
7.493
−4.110
1.00
42.64
C
ATOM
2713
CB
LYS
E
92
−28.060
8.202
−4.052
1.00
42.47
C
ATOM
2714
CG
LYS
E
92
−29.239
7.224
−4.140
1.00
43.53
C
ATOM
2715
CD
LYS
E
92
−30.550
7.958
−4.021
1.00
46.74
C
ATOM
2716
CE
LYS
E
92
−31.751
7.118
−4.485
1.00
49.77
C
ATOM
2717
NZ
LYS
E
92
−32.896
8.037
−4.867
1.00
50.02
N
ATOM
2718
C
LYS
E
92
−25.573
8.457
−4.501
1.00
40.10
C
ATOM
2719
O
LYS
E
92
−25.796
9.458
−5.136
1.00
38.93
O
ATOM
2720
N
MET
E
93
−24.349
8.133
−4.122
1.00
39.27
N
ATOM
2721
CA
MET
E
93
−23.235
9.034
−4.437
1.00
36.91
C
ATOM
2722
CB
MET
E
93
−22.119
8.773
−3.412
1.00
37.41
C
ATOM
2723
CG
MET
E
93
−22.479
9.291
−1.964
1.00
31.53
C
ATOM
2724
SD
MET
E
93
−22.304
11.036
−1.841
1.00
28.70
S
ATOM
2725
CE
MET
E
93
−20.484
11.169
−1.694
1.00
34.53
C
ATOM
2726
C
MET
E
93
−22.765
8.825
−5.899
1.00
37.37
C
ATOM
2727
O
MET
E
93
−22.918
7.710
−6.447
1.00
36.91
O
ATOM
2728
N
PRO
E
94
−22.165
9.857
−6.536
1.00
36.94
N
ATOM
2729
CA
PRO
E
94
−21.564
9.531
−7.838
1.00
37.19
C
ATOM
2730
CB
PRO
E
94
−21.254
10.895
−8.461
1.00
36.24
C
ATOM
2731
CG
PRO
E
94
−20.950
11.736
−7.389
1.00
38.23
C
ATOM
2732
CD
PRO
E
94
−21.988
11.296
−6.224
1.00
39.37
C
ATOM
2733
C
PRO
E
94
−20.320
8.631
−7.811
1.00
36.57
C
ATOM
2734
O
PRO
E
94
−19.810
8.256
−6.737
1.00
35.69
O
ATOM
2735
N
GLU
E
95
−19.914
8.226
−9.014
1.00
35.80
N
ATOM
2736
CA
GLU
E
95
−18.753
7.391
−9.223
1.00
35.27
C
ATOM
2737
CB
GLU
E
95
−18.713
6.907
−10.675
1.00
35.38
C
ATOM
2738
CG
GLU
E
95
−17.861
5.669
−10.825
1.00
38.08
C
ATOM
2739
CD
GLU
E
95
−17.766
5.134
−12.274
1.00
40.77
C
ATOM
2740
OE1
GLU
E
95
−18.593
5.507
−13.149
1.00
46.42
O
ATOM
2741
OE2
GLU
E
95
−16.839
4.316
−12.507
1.00
46.20
O
ATOM
2742
C
GLU
E
95
−17.498
8.196
−8.913
1.00
31.36
C
ATOM
2743
O
GLU
E
95
−17.424
9.384
−9.207
1.00
31.21
O
ATOM
2744
N
CYS
E
96
−16.527
7.556
−8.294
1.00
29.43
N
ATOM
2745
CA
CYS
E
96
−15.284
8.265
−7.889
1.00
28.13
C
ATOM
2746
CB
CYS
E
96
−14.508
7.365
−6.971
1.00
27.21
C
ATOM
2747
SG
CYS
E
96
−12.849
7.953
−6.549
1.00
27.50
S
ATOM
2748
C
CYS
E
96
−14.508
8.471
−9.175
1.00
27.70
C
ATOM
2749
O
CYS
E
96
−14.232
7.501
−9.836
1.00
27.84
O
ATOM
2750
N
TYR
E
97
−14.181
9.703
−9.531
1.00
26.25
N
ATOM
2751
CA
TYR
E
97
−13.414
9.932
−10.745
1.00
27.57
C
ATOM
2752
CB
TYR
E
97
−13.183
11.447
−10.963
1.00
27.83
C
ATOM
2753
CG
TYR
E
97
−12.434
11.765
−12.280
1.00
27.33
C
ATOM
2754
CD1
TYR
E
97
−13.144
11.989
−13.471
1.00
27.83
C
ATOM
2755
CE1
TYR
E
97
−12.478
12.267
−14.677
1.00
27.62
C
ATOM
2756
CZ
TYR
E
97
−11.082
12.321
−14.685
1.00
28.27
C
ATOM
2757
OH
TYR
E
97
−10.432
12.605
−15.880
1.00
25.71
O
ATOM
2758
CE2
TYR
E
97
−10.354
12.103
−13.511
1.00
24.85
C
ATOM
2759
CD2
TYR
E
97
−11.038
11.817
−12.316
1.00
26.24
C
ATOM
2760
C
TYR
E
97
−12.073
9.203
−10.758
1.00
28.02
C
ATOM
2761
O
TYR
E
97
−11.659
8.599
−11.805
1.00
27.69
O
ATOM
2762
N
PHE
E
98
−11.400
9.205
−9.593
1.00
28.03
N
ATOM
2763
CA
PHE
E
98
−10.056
8.574
−9.539
1.00
28.74
C
ATOM
2764
CB
PHE
E
98
−9.209
9.067
−8.348
1.00
27.42
C
ATOM
2765
CG
PHE
E
98
−8.924
10.529
−8.429
1.00
27.64
C
ATOM
2766
CD1
PHE
E
98
−7.877
11.006
−9.197
1.00
23.70
C
ATOM
2767
CE1
PHE
E
98
−7.658
12.398
−9.317
1.00
26.52
C
ATOM
2768
CZ
PHE
E
98
−8.497
13.304
−8.674
1.00
28.09
C
ATOM
2769
CE2
PHE
E
98
−9.562
12.831
−7.920
1.00
28.78
C
ATOM
2770
CD2
PHE
E
98
−9.789
11.454
−7.817
1.00
28.89
C
ATOM
2771
C
PHE
E
98
−10.123
7.079
−9.657
1.00
29.39
C
ATOM
2772
O
PHE
E
98
−9.326
6.464
−10.377
1.00
29.21
O
ATOM
2773
N
TYR
E
99
−11.082
6.463
−8.980
1.00
30.20
N
ATOM
2774
CA
TYR
E
99
−11.204
5.035
−9.147
1.00
31.46
C
ATOM
2775
CB
TYR
E
99
−12.314
4.476
−8.289
1.00
32.90
C
ATOM
2776
CG
TYR
E
99
−12.154
3.001
−8.112
1.00
35.08
C
ATOM
2777
CD1
TYR
E
99
−11.241
2.484
−7.198
1.00
34.37
C
ATOM
2778
CE1
TYR
E
99
−11.089
1.106
−7.057
1.00
36.08
C
ATOM
2779
CZ
TYR
E
99
−11.825
0.251
−7.867
1.00
36.77
C
ATOM
2780
OH
TYR
E
99
−11.700
−1.119
−7.754
1.00
39.62
O
ATOM
2781
CE2
TYR
E
99
−12.712
0.738
−8.781
1.00
38.21
C
ATOM
2782
CD2
TYR
E
99
−12.871
2.107
−8.916
1.00
36.36
C
ATOM
2783
C
TYR
E
99
−11.462
4.646
−10.616
1.00
32.82
C
ATOM
2784
O
TYR
E
99
−10.908
3.659
−11.120
1.00
32.79
O
ATOM
2785
N
SER
E
100
−12.332
5.389
−11.280
1.00
33.86
N
ATOM
2786
CA
SER
E
100
−12.687
5.068
−12.670
1.00
35.38
C
ATOM
2787
CB
SER
E
100
−13.824
5.936
−13.129
1.00
35.98
C
ATOM
2788
OG
SER
E
100
−14.948
5.495
−12.418
1.00
42.18
O
ATOM
2789
C
SER
E
100
−11.552
5.261
−13.634
1.00
34.57
C
ATOM
2790
O
SER
E
100
−11.311
4.382
−14.485
1.00
35.38
O
ATOM
2791
N
LYS
E
101
−10.898
6.419
−13.544
1.00
33.48
N
ATOM
2792
CA
LYS
E
101
−9.846
6.763
−14.475
1.00
33.32
C
ATOM
2793
CB
LYS
E
101
−9.693
8.273
−14.596
1.00
32.76
C
ATOM
2794
CG
LYS
E
101
−10.919
8.921
−15.140
1.00
35.61
C
ATOM
2795
CD
LYS
E
101
−11.059
8.628
−16.629
1.00
39.82
C
ATOM
2796
CE
LYS
E
101
−12.355
9.151
−17.199
1.00
42.68
C
ATOM
2797
NZ
LYS
E
101
−12.484
8.574
−18.576
1.00
42.39
N
ATOM
2798
C
LYS
E
101
−8.497
6.108
−14.191
1.00
33.88
C
ATOM
2799
O
LYS
E
101
−7.759
5.832
−15.139
1.00
33.90
O
ATOM
2800
N
PHE
E
102
−8.181
5.861
−12.912
1.00
32.56
N
ATOM
2801
CA
PHE
E
102
−6.835
5.447
−12.503
1.00
31.86
C
ATOM
2802
CB
PHE
E
102
−6.209
6.431
−11.495
1.00
31.71
C
ATOM
2803
CG
PHE
E
102
−5.911
7.752
−12.070
1.00
29.81
C
ATOM
2804
CD1
PHE
E
102
−4.669
8.009
−12.648
1.00
30.67
C
ATOM
2805
CE1
PHE
E
102
−4.383
9.228
−13.206
1.00
31.08
C
ATOM
2806
CZ
PHE
E
102
−5.313
10.210
−13.239
1.00
29.85
C
ATOM
2807
CE2
PHE
E
102
−6.592
9.960
−12.677
1.00
32.46
C
ATOM
2808
CD2
PHE
E
102
−6.855
8.741
−12.088
1.00
30.80
C
ATOM
2809
C
PHE
E
102
−6.867
4.069
−11.922
1.00
32.42
C
ATOM
2810
O
PHE
E
102
−5.820
3.478
−11.671
1.00
33.02
O
ATOM
2811
N
GLY
E
103
−8.068
3.525
−11.746
1.00
31.07
N
ATOM
2812
CA
GLY
E
103
−8.200
2.204
−11.153
1.00
31.68
C
ATOM
2813
C
GLY
E
103
−7.805
2.110
−9.684
1.00
31.41
C
ATOM
2814
O
GLY
E
103
−7.611
1.003
−9.152
1.00
31.06
O
ATOM
2815
N
GLU
E
104
−7.663
3.257
−9.019
1.00
29.83
N
ATOM
2816
CA
GLU
E
104
−7.265
3.253
−7.620
1.00
30.89
C
ATOM
2817
CB
GLU
E
104
−5.732
3.019
−7.469
1.00
29.78
C
ATOM
2818
CG
GLU
E
104
−4.916
4.241
−7.780
1.00
33.61
C
ATOM
2819
CD
GLU
E
104
−3.398
4.038
−7.615
1.00
36.14
C
ATOM
2820
OE1
GLU
E
104
−2.709
3.917
−8.663
1.00
46.90
O
ATOM
2821
OE2
GLU
E
104
−2.887
3.988
−6.469
1.00
39.91
O
ATOM
2822
C
GLU
E
104
−7.690
4.595
−7.001
1.00
29.61
C
ATOM
2823
O
GLU
E
104
−7.924
5.573
−7.706
1.00
28.68
O
ATOM
2824
N
CYS
E
105
−7.825
4.607
−5.671
1.00
29.11
N
ATOM
2825
CA
CYS
E
105
−8.246
5.809
−4.944
1.00
28.00
C
ATOM
2826
CB
CYS
E
105
−9.773
5.777
−4.754
1.00
28.22
C
ATOM
2827
SG
CYS
E
105
−10.400
7.210
−3.819
1.00
26.77
S
ATOM
2828
C
CYS
E
105
−7.535
5.815
−3.584
1.00
27.95
C
ATOM
2829
O
CYS
E
105
−7.514
4.801
−2.897
1.00
25.98
O
ATOM
2830
N
SER
E
106
−6.951
6.947
−3.213
1.00
27.07
N
ATOM
2831
CA
SER
E
106
−6.105
7.032
−1.999
1.00
27.68
C
ATOM
2832
CB
SER
E
106
−5.147
8.214
−2.106
1.00
28.93
C
ATOM
2833
OG
SER
E
106
−4.158
8.061
−3.082
1.00
32.26
O
ATOM
2834
C
SER
E
106
−6.926
7.262
−0.708
1.00
27.48
C
ATOM
2835
O
SER
E
106
−6.392
7.202
0.389
1.00
25.89
O
ATOM
2836
N
ASN
E
107
−8.224
7.543
−0.847
1.00
27.00
N
ATOM
2837
CA
ASN
E
107
−9.022
7.880
0.340
1.00
27.38
C
ATOM
2838
CB
ASN
E
107
−10.085
8.933
−0.017
1.00
25.51
C
ATOM
2839
CG
ASN
E
107
−10.890
9.409
1.197
1.00
27.22
C
ATOM
2840
OD1
ASN
E
107
−10.602
9.029
2.353
1.00
25.23
O
ATOM
2841
ND2
ASN
E
107
−11.888
10.253
0.951
1.00
23.13
N
ATOM
2842
C
ASN
E
107
−9.615
6.620
0.922
1.00
26.72
C
ATOM
2843
O
ASN
E
107
−10.527
6.051
0.323
1.00
27.32
O
ATOM
2844
N
LYS
E
108
−9.112
6.171
2.083
1.00
27.29
N
ATOM
2845
CA
LYS
E
108
−9.675
4.967
2.740
1.00
28.64
C
ATOM
2846
CB
LYS
E
108
−9.005
4.634
4.084
1.00
29.14
C
ATOM
2847
CG
LYS
E
108
−7.538
4.411
4.047
1.00
32.85
C
ATOM
2848
CD
LYS
E
108
−7.002
4.055
5.424
1.00
35.90
C
ATOM
2849
CE
LYS
E
108
−5.512
4.069
5.365
1.00
36.28
C
ATOM
2850
NZ
LYS
E
108
−4.896
4.177
6.709
1.00
38.68
N
ATOM
2851
C
LYS
E
108
−11.169
5.115
3.022
1.00
28.54
C
ATOM
2852
O
LYS
E
108
−11.874
4.132
3.143
1.00
28.63
O
ATOM
2853
N
GLU
E
109
−11.635
6.345
3.166
1.00
28.33
N
ATOM
2854
CA
GLU
E
109
−13.047
6.575
3.462
1.00
29.24
C
ATOM
2855
CB
GLU
E
109
−13.216
7.516
4.691
1.00
30.12
C
ATOM
2856
CG
GLU
E
109
−12.867
6.879
6.081
1.00
35.42
C
ATOM
2857
CD
GLU
E
109
−11.375
6.836
6.374
1.00
39.45
C
ATOM
2858
OE1
GLU
E
109
−10.711
7.883
6.247
1.00
43.20
O
ATOM
2859
OE2
GLU
E
109
−10.867
5.756
6.753
1.00
42.90
O
ATOM
2860
C
GLU
E
109
−13.729
7.224
2.273
1.00
26.67
C
ATOM
2861
O
GLU
E
109
−14.689
7.956
2.466
1.00
27.77
O
ATOM
2862
N
CYS
E
110
−13.258
6.987
1.039
1.00
25.08
N
ATOM
2863
CA
CYS
E
110
−13.932
7.567
−0.125
1.00
22.73
C
ATOM
2864
CB
CYS
E
110
−13.376
7.014
−1.473
1.00
22.38
C
ATOM
2865
SG
CYS
E
110
−14.027
7.983
−2.730
1.00
25.05
S
ATOM
2866
C
CYS
E
110
−15.435
7.227
−0.065
1.00
23.60
C
ATOM
2867
O
CYS
E
110
−15.792
6.066
0.033
1.00
22.90
O
ATOM
2868
N
PRO
E
111
−16.302
8.231
−0.103
1.00
25.41
N
ATOM
2869
CA
PRO
E
111
−17.756
7.947
−0.173
1.00
26.31
C
ATOM
2870
CB
PRO
E
111
−18.338
9.189
0.451
1.00
25.57
C
ATOM
2871
CG
PRO
E
111
−17.444
10.247
−0.107
1.00
26.34
C
ATOM
2872
CD
PRO
E
111
−16.056
9.690
−0.017
1.00
24.13
C
ATOM
2873
C
PRO
E
111
−18.303
7.806
−1.607
1.00
28.09
C
ATOM
2874
O
PRO
E
111
−19.532
7.606
−1.781
1.00
29.35
O
ATOM
2875
N
PHE
E
112
−17.433
7.912
−2.620
1.00
27.81
N
ATOM
2876
CA
PHE
E
112
−17.882
7.841
−4.035
1.00
28.90
C
ATOM
2877
CB
PHE
E
112
−17.134
8.827
−4.915
1.00
27.89
C
ATOM
2878
CG
PHE
E
112
−17.352
10.241
−4.519
1.00
29.43
C
ATOM
2879
CD1
PHE
E
112
−18.534
10.897
−4.864
1.00
29.20
C
ATOM
2880
CE1
PHE
E
112
−18.766
12.200
−4.465
1.00
31.44
C
ATOM
2881
CZ
PHE
E
112
−17.793
12.893
−3.678
1.00
33.51
C
ATOM
2882
CE2
PHE
E
112
−16.595
12.222
−3.336
1.00
36.00
C
ATOM
2883
CD2
PHE
E
112
−16.403
10.905
−3.756
1.00
32.00
C
ATOM
2884
C
PHE
E
112
−17.782
6.434
−4.538
1.00
30.08
C
ATOM
2885
O
PHE
E
112
−17.062
5.634
−3.968
1.00
29.81
O
ATOM
2886
N
LEU
E
113
−18.581
6.077
−5.546
1.00
32.91
N
ATOM
2887
CA
LEU
E
113
−18.669
4.649
−5.892
1.00
35.90
C
ATOM
2888
CB
LEU
E
113
−19.833
4.379
−6.828
1.00
37.47
C
ATOM
2889
CG
LEU
E
113
−21.292
4.429
−6.377
1.00
41.02
C
ATOM
2890
CD1
LEU
E
113
−21.876
3.209
−7.053
1.00
44.71
C
ATOM
2891
CD2
LEU
E
113
−21.536
4.386
−4.840
1.00
43.90
C
ATOM
2892
C
LEU
E
113
−17.391
4.132
−6.538
1.00
36.02
C
ATOM
2893
O
LEU
E
113
−16.829
4.764
−7.434
1.00
36.35
O
ATOM
2894
N
HIS
E
114
−16.931
2.977
−6.089
1.00
36.99
N
ATOM
2895
CA
HIS
E
114
−15.750
2.409
−6.678
1.00
37.82
C
ATOM
2896
CB
HIS
E
114
−14.693
2.014
−5.614
1.00
36.44
C
ATOM
2897
CG
HIS
E
114
−13.917
3.183
−5.031
1.00
30.06
C
ATOM
2898
ND1
HIS
E
114
−12.967
3.009
−4.046
1.00
27.67
N
ATOM
2899
CE1
HIS
E
114
−12.448
4.177
−3.706
1.00
29.37
C
ATOM
2900
NE2
HIS
E
114
−12.992
5.119
−4.459
1.00
21.70
N
ATOM
2901
CD2
HIS
E
114
−13.942
4.521
−5.284
1.00
28.54
C
ATOM
2902
C
HIS
E
114
−16.206
1.255
−7.575
1.00
41.48
C
ATOM
2903
O
HIS
E
114
−16.540
0.141
−7.109
1.00
41.75
O
ATOM
2904
N
ILE
E
115
−16.225
1.542
−8.874
1.00
45.09
N
ATOM
2905
CA
ILE
E
115
−16.770
0.592
−9.829
1.00
48.98
C
ATOM
2906
CB
ILE
E
115
−17.879
1.233
−10.682
1.00
48.73
C
ATOM
2907
CG1
ILE
E
115
−19.018
1.650
−9.769
1.00
49.30
C
ATOM
2908
CD1
ILE
E
115
−20.108
2.486
−10.414
1.00
52.31
C
ATOM
2909
CG2
ILE
E
115
−18.429
0.233
−11.703
1.00
50.04
C
ATOM
2910
C
ILE
E
115
−15.698
−0.097
−10.663
1.00
51.45
C
ATOM
2911
O
ILE
E
115
−14.888
0.552
−11.342
1.00
51.91
O
ATOM
2912
N
ASP
E
116
−15.713
−1.426
−10.604
1.00
55.09
N
ATOM
2913
CA
ASP
E
116
−14.838
−2.269
−11.446
1.00
58.10
C
ATOM
2914
CB
ASP
E
116
−14.477
−3.551
−10.704
1.00
57.84
C
ATOM
2915
CG
ASP
E
116
−13.320
−3.361
−9.748
1.00
59.39
C
ATOM
2916
OD1
ASP
E
116
−12.283
−2.772
−10.153
1.00
58.51
O
ATOM
2917
OD2
ASP
E
116
−13.450
−3.816
−8.591
1.00
61.50
O
ATOM
2918
C
ASP
E
116
−15.346
−2.612
−12.862
1.00
59.18
C
ATOM
2919
O
ASP
E
116
−14.564
−2.484
−13.826
1.00
59.43
O
ATOM
2920
N
PRO
E
117
−16.632
−3.068
−12.982
1.00
60.29
N
ATOM
2921
CA
PRO
E
117
−17.292
−3.632
−14.189
1.00
61.09
C
ATOM
2922
CB
PRO
E
117
−18.750
−3.133
−14.046
1.00
61.33
C
ATOM
2923
CG
PRO
E
117
−18.991
−3.196
−12.535
1.00
60.80
C
ATOM
2924
CD
PRO
E
117
−17.592
−3.089
−11.852
1.00
60.62
C
ATOM
2925
C
PRO
E
117
−16.713
−3.318
−15.593
1.00
62.20
C
ATOM
2926
O
PRO
E
117
−16.501
−2.150
−15.971
1.00
62.74
O
ATOM
2927
OXT
PRO
E
117
−16.466
−4.245
−16.386
1.00
62.43
O
ATOM
2928
ZN
ZN
E
502
−12.635
7.037
−4.437
1.00
27.25
ZN
ATOM
2929
ZN
ZN
E
501
−26.608
21.029
−5.804
1.00
39.92
ZN
ATOM
2930
OH2
HOH
W
1
−17.549
40.654
24.318
1.00
31.56
ATOM
2931
OH2
HOH
W
2
17.362
20.052
−2.479
1.00
25.50
ATOM
2932
OH2
HOH
W
3
−2.011
29.501
11.491
1.00
30.11
ATOM
2933
OH2
HOH
W
4
−1.231
11.877
4.344
1.00
33.10
ATOM
2934
OH2
HOH
W
5
−15.837
4.131
−2.007
1.00
34.35
ATOM
2935
OH2
HOH
W
6
−18.878
24.607
32.037
1.00
37.33
ATOM
2936
OH2
HOH
W
7
−8.008
1.692
−4.434
1.00
36.76
ATOM
2937
OH2
HOH
W
8
0.580
21.608
13.618
1.00
37.53
ATOM
2938
OH2
HOH
W
9
16.380
17.882
10.672
1.00
37.87
ATOM
2939
OH2
HOH
W
10
−22.130
37.815
21.073
1.00
35.89
ATOM
2940
OH2
HOH
W
11
4.673
13.758
−32.750
1.00
33.95
ATOM
2941
OH2
HOH
W
12
−20.499
24.465
5.437
1.00
28.59
ATOM
2942
OH2
HOH
W
13
23.425
25.428
−2.508
1.00
37.38
ATOM
2943
OH2
HOH
W
14
−14.983
15.840
−4.699
1.00
46.26
ATOM
2944
OH2
HOH
W
15
−10.233
9.257
−27.822
1.00
38.63
ATOM
2945
OH2
HOH
W
16
−21.192
34.424
12.062
1.00
37.61
ATOM
2946
OH2
HOH
W
17
0.053
26.141
−3.950
1.00
54.93
ATOM
2947
OH2
HOH
W
18
−5.394
4.386
9.736
1.00
37.09
ATOM
2948
OH2
HOH
W
19
−8.975
14.385
−2.075
1.00
37.40
ATOM
2949
OH2
HOH
W
20
−11.483
11.732
−4.064
1.00
48.02
ATOM
2950
OH2
HOH
W
21
8.538
14.250
−15.163
1.00
45.77
ATOM
2951
OH2
HOH
W
22
−13.507
26.363
33.684
1.00
36.52
ATOM
2952
OH2
HOH
W
23
−22.909
39.389
25.431
1.00
51.50
ATOM
2953
OH2
HOH
W
24
−6.016
34.962
15.554
1.00
40.08
ATOM
2954
OH2
HOH
W
25
−27.799
20.311
13.356
1.00
40.64
ATOM
2955
OH2
HOH
W
26
−9.659
40.204
28.277
1.00
50.22
ATOM
2956
OH2
HOH
W
27
−22.574
19.101
15.450
1.00
47.34
ATOM
2957
OH2
HOH
W
28
−37.126
26.264
−0.600
1.00
39.56
ATOM
2958
OH2
HOH
W
29
−9.898
30.112
1.970
1.00
56.19
ATOM
2959
OH2
HOH
W
30
14.875
14.573
−3.591
1.00
37.15
ATOM
2960
OH2
HOH
W
31
−1.553
2.908
9.016
1.00
47.01
ATOM
2961
OH2
HOH
W
32
−21.032
30.547
7.051
1.00
40.04
ATOM
2962
OH2
HOH
W
33
−0.209
7.321
−31.105
1.00
38.83
ATOM
2963
OH2
HOH
W
34
−9.687
37.554
14.224
1.00
43.90
ATOM
2964
OH2
HOH
W
35
−22.793
14.964
−8.325
1.00
50.86
ATOM
2965
OH2
HOH
W
36
−8.615
28.359
−20.387
1.00
40.23
ATOM
2966
OH2
HOH
W
37
−14.482
27.081
1.103
1.00
48.65
ATOM
2967
OH2
HOH
W
38
−21.411
9.115
−11.631
1.00
44.01
ATOM
2968
OH2
HOH
W
39
−11.464
1.095
−12.508
1.00
45.05
ATOM
2969
OH2
HOH
W
40
−0.402
15.047
−34.444
1.00
41.68
ATOM
2970
OH2
HOH
W
41
13.970
29.824
−18.438
1.00
46.66
ATOM
2971
OH2
HOH
W
42
0.010
18.179
−1.761
1.00
44.33
ATOM
2972
OH2
HOH
W
43
−24.141
42.098
27.887
1.00
62.32
ATOM
2973
OH2
HOH
W
44
−28.543
34.801
14.268
1.00
48.79
ATOM
2974
OH2
HOH
W
45
−19.052
36.669
14.149
1.00
43.38
ATOM
2975
OH2
HOH
W
46
−21.027
5.982
−0.187
1.00
43.29
ATOM
2976
OH2
HOH
W
47
−11.461
10.710
26.650
1.00
45.24
ATOM
2977
OH2
HOH
W
48
−32.578
9.524
−0.486
1.00
62.86
ATOM
2978
OH2
HOH
W
49
−25.755
40.650
29.914
1.00
48.32
ATOM
2979
OH2
HOH
W
50
−1.405
33.346
−4.925
1.00
60.35
ATOM
2980
OH2
HOH
W
51
−5.133
15.525
3.092
1.00
32.86
ATOM
2981
OH2
HOH
W
52
−13.645
18.564
32.922
1.00
50.50
ATOM
2982
OH2
HOH
W
53
−12.789
9.521
30.610
1.00
53.37
ATOM
2983
OH2
HOH
W
54
−9.573
17.794
28.093
1.00
49.45
ATOM
2984
OH2
HOH
W
55
−12.428
24.883
−14.429
1.00
43.17
ATOM
2985
OH2
HOH
W
56
−27.927
17.852
13.258
1.00
49.70
ATOM
2986
OH2
HOH
W
57
2.388
8.886
18.777
1.00
45.10
ATOM
2987
OH2
HOH
W
58
−12.077
0.367
−3.463
1.00
44.30
ATOM
2988
OW0
HOH
W
59
1.704
8.508
14.181
1.00
30.60
ATOM
2989
OW0
HOH
W
60
−7.056
24.808
−1.087
1.00
33.17
ATOM
2990
OW0
HOH
W
61
−12.392
10.737
−1.805
1.00
34.81
ATOM
2991
OW0
HOH
W
62
−2.525
5.036
5.866
1.00
36.96
ATOM
2992
OW0
HOH
W
63
−12.292
41.162
28.775
1.00
28.15
ATOM
2993
OW0
HOH
W
64
−7.563
19.859
7.620
1.00
29.26
ATOM
2994
OW0
HOH
W
65
−15.842
2.676
−14.366
1.00
53.47
ATOM
2995
OW0
HOH
W
66
−31.515
20.265
−4.155
1.00
35.35
ATOM
2996
OW0
HOH
W
67
−3.936
8.455
−26.236
1.00
32.60
ATOM
2997
OW0
HOH
W
68
−11.026
3.554
−0.830
1.00
40.04
ATOM
2998
OW0
HOH
W
69
−19.858
20.494
4.314
1.00
31.44
ATOM
2999
OW0
HOH
W
70
8.620
14.453
−26.618
1.00
35.55
ATOM
3000
OW0
HOH
W
71
−2.280
13.892
6.137
1.00
38.09
ATOM
3001
OW0
HOH
W
72
4.718
30.472
−24.432
1.00
38.03
ATOM
3002
OW0
HOH
W
73
−5.982
20.628
−1.464
1.00
46.93
ATOM
3003
OW0
HOH
W
74
3.340
20.902
4.854
1.00
37.94
ATOM
3004
OW0
HOH
W
75
18.667
21.796
−0.422
1.00
35.98
ATOM
3005
OW0
HOH
W
76
−9.114
7.695
8.920
1.00
46.41
ATOM
3006
OW0
HOH
W
77
−2.725
9.410
−24.189
1.00
35.50
ATOM
3007
OW0
HOH
W
78
26.980
18.899
12.829
1.00
31.81
ATOM
3008
OW0
HOH
W
79
17.646
21.683
3.437
1.00
31.91
ATOM
3009
OW0
HOH
W
80
−8.571
17.509
−24.553
1.00
34.33
ATOM
3010
OW0
HOH
W
81
−7.652
32.985
8.726
1.00
43.98
ATOM
3011
OW0
HOH
W
82
−2.625
5.632
−10.150
1.00
36.97
ATOM
3012
OW0
HOH
W
83
−12.028
32.276
7.227
1.00
39.35
ATOM
3013
OW0
HOH
W
84
−33.711
27.130
−3.174
1.00
42.56
ATOM
3014
OW0
HOH
W
85
−17.611
17.995
17.184
1.00
34.50
ATOM
3015
OW0
HOH
W
86
−19.109
18.971
27.592
1.00
35.69
ATOM
3016
OW0
HOH
W
87
−21.991
22.413
5.160
1.00
39.27
ATOM
3017
OW0
HOH
W
88
13.659
19.242
−8.046
1.00
47.60
ATOM
3018
OW0
HOH
W
89
−10.339
18.565
25.687
1.00
42.43
ATOM
3019
OW0
HOH
W
90
1.970
26.030
6.048
1.00
40.39
ATOM
3020
OW0
HOH
W
91
−8.765
21.673
0.433
1.00
37.72
ATOM
3021
OW0
HOH
W
92
−20.850
26.325
2.908
1.00
56.35
ATOM
3022
OW0
HOH
W
93
−12.366
9.191
20.494
1.00
34.84
ATOM
3023
OW0
HOH
W
94
−9.896
37.447
29.444
1.00
34.76
ATOM
3024
OW0
HOH
W
95
−17.552
18.919
−5.164
1.00
41.85
ATOM
3025
OW0
HOH
W
96
6.232
22.128
−7.201
1.00
41.21
ATOM
3026
OW0
HOH
W
97
−6.797
16.849
0.240
1.00
36.86
ATOM
3027
OW0
HOH
W
98
1.161
18.227
−5.047
1.00
57.06
ATOM
3028
OW0
HOH
W
99
2.288
6.066
6.745
1.00
37.06
ATOM
3029
OW0
HOH
W
100
−29.295
32.635
11.013
1.00
43.96
ATOM
3030
OW0
HOH
W
101
−28.464
25.424
7.690
1.00
45.49
ATOM
3031
OW0
HOH
W
102
−30.152
13.612
−9.680
1.00
43.80
ATOM
3032
OW0
HOH
W
103
−1.599
6.868
17.329
1.00
42.18
ATOM
3033
OW0
HOH
W
104
−1.887
24.290
18.531
1.00
44.13
ATOM
3034
OW0
HOH
W
105
27.796
19.455
3.634
1.00
48.46
ATOM
3035
OW0
HOH
W
106
−8.030
10.167
−31.332
1.00
48.25
ATOM
3036
OW0
HOH
W
107
−2.985
30.050
15.427
1.00
49.05
ATOM
3037
OW0
HOH
W
108
−1.504
32.061
−21.190
1.00
44.44
ATOM
3038
OW0
HOH
W
109
6.204
30.000
−16.933
1.00
42.31
ATOM
3039
OW0
HOH
W
110
−4.122
20.605
23.054
1.00
41.35
ATOM
3040
OW0
HOH
W
111
−9.885
40.341
21.208
1.00
43.88
ATOM
3041
OW0
HOH
W
112
−20.863
15.617
19.646
1.00
52.25
ATOM
3042
OW0
HOH
W
113
−27.560
21.675
7.325
1.00
36.97
ATOM
3043
OW0
HOH
W
114
−13.970
38.207
15.196
1.00
36.20
ATOM
3044
OW0
HOH
W
115
−10.257
8.670
16.396
1.00
44.34
ATOM
3045
OW0
HOH
W
116
−26.779
32.379
17.536
1.00
46.46
ATOM
3046
OW0
HOH
W
117
14.378
29.066
−14.762
1.00
43.06
ATOM
3047
OW0
HOH
W
118
−19.826
37.668
18.886
1.00
43.88
ATOM
3048
OW0
HOH
W
119
7.366
26.176
−46.829
1.00
49.36
ATOM
3049
OW0
HOH
W
120
−29.626
18.951
11.431
1.00
43.10
ATOM
3050
OW0
HOH
W
121
−14.313
21.458
−18.725
1.00
40.54
ATOM
3051
OW0
HOH
W
122
−0.759
26.600
1.740
1.00
45.86
ATOM
3052
OW0
HOH
W
123
−2.111
2.918
−16.154
1.00
46.67
ATOM
3053
OW0
HOH
W
124
3.331
26.748
−37.297
1.00
48.14
ATOM
3054
OW0
HOH
W
125
−2.436
28.999
−11.573
1.00
46.74
ATOM
3055
OW0
HOH
W
126
10.219
29.479
4.241
1.00
56.66
ATOM
3056
OW0
HOH
W
127
8.822
19.046
9.037
1.00
46.32
ATOM
3057
OW0
HOH
W
128
−2.874
16.046
4.626
1.00
37.70
ATOM
3058
OW0
HOH
W
129
−0.279
3.806
5.506
1.00
52.87
ATOM
3059
OW0
HOH
W
130
−32.360
19.413
1.195
1.00
50.24
ATOM
3060
OW0
HOH
W
131
−6.511
17.061
−7.831
1.00
39.09
ATOM
3061
OW0
HOH
W
132
2.417
23.144
8.408
1.00
44.56
ATOM
3062
OW0
HOH
W
133
−16.608
10.384
−12.085
1.00
45.07
ATOM
3063
OW0
HOH
W
134
−2.846
29.191
3.912
1.00
46.72
ATOM
3064
OW0
HOH
W
135
−17.527
21.749
4.420
1.00
43.90
ATOM
3065
OW0
HOH
W
136
−23.992
22.344
21.494
1.00
41.44
ATOM
3066
OW0
HOH
W
137
−23.795
27.206
3.547
1.00
54.65
ATOM
3067
OW0
HOH
W
138
−29.116
14.677
5.068
1.00
51.65
ATOM
3068
OW0
HOH
W
139
9.313
19.837
−4.271
1.00
55.48
ATOM
3069
OW0
HOH
W
140
−15.044
19.642
5.067
1.00
42.06
ATOM
3070
OW0
HOH
W
141
3.974
1.933
15.902
1.00
52.22
ATOM
3071
OW0
HOH
W
142
0.091
17.275
4.399
1.00
49.56
ATOM
3072
OW0
HOH
W
143
−25.537
21.936
14.509
1.00
42.90
ATOM
3073
OW0
HOH
W
144
−15.697
22.135
2.544
1.00
53.67
ATOM
3074
OW0
HOH
W
145
−16.772
39.732
17.788
1.00
46.17
ATOM
3075
OW0
HOH
W
146
−22.834
23.263
26.427
1.00
44.02
ATOM
3076
OW0
HOH
W
147
−4.433
30.459
1.897
1.00
54.37
ATOM
3077
OW0
HOH
W
148
10.805
29.216
−12.444
1.00
46.47
ATOM
3078
OW0
HOH
W
149
9.875
15.248
−22.074
1.00
39.59
ATOM
3079
OW0
HOH
W
150
19.274
21.111
10.902
1.00
45.24
ATOM
3080
OW0
HOH
W
151
−23.788
22.513
−8.738
1.00
50.90
ATOM
3081
OW0
HOH
W
152
−18.012
12.403
12.283
1.00
58.78
ATOM
3082
OW0
HOH
W
153
−23.602
19.922
19.962
1.00
46.19
ATOM
3083
OW0
HOH
W
154
19.294
22.358
13.809
1.00
47.46
ATOM
3084
OW0
HOH
W
155
−16.570
11.359
31.299
1.00
48.30
ATOM
3085
OW0
HOH
W
156
−10.846
16.772
31.754
1.00
51.00
ATOM
3086
OW0
HOH
W
157
−6.781
8.331
−29.531
1.00
48.71
ATOM
3087
OW0
HOH
W
158
−25.361
37.429
21.866
1.00
53.58
ATOM
3088
OW0
HOH
W
159
−25.833
29.686
21.358
1.00
50.75
ATOM
3089
OW0
HOH
W
160
−47.219
5.581
−4.792
1.00
56.63
ATOM
3090
OW0
HOH
W
161
6.673
27.621
−10.556
1.00
44.41
ATOM
3091
OW0
HOH
W
162
0.676
23.720
14.657
1.00
45.33
ATOM
3092
OW0
HOH
W
163
−17.977
1.385
−4.066
1.00
49.80
ATOM
3093
OW0
HOH
W
164
6.273
19.800
−5.128
1.00
41.05
ATOM
3094
OW0
HOH
W
165
1.774
1.455
12.183
1.00
53.13
ATOM
3095
OW0
HOH
W
166
−47.850
5.153
0.253
1.00
54.28
ATOM
3096
OW0
HOH
W
167
0.571
0.928
−8.183
1.00
57.03
ATOM
3097
OW0
HOH
W
168
−15.657
41.281
19.809
1.00
33.76
ATOM
3098
OW0
HOH
W
169
−1.350
19.580
18.894
1.00
48.90
ATOM
3099
OW0
HOH
W
170
−22.822
18.718
−8.056
1.00
46.46
ATOM
3100
OW0
HOH
W
171
−27.476
27.793
21.291
1.00
44.42
ATOM
3101
OW0
HOH
W
172
−13.995
8.378
13.827
1.00
46.07
ATOM
3102
OW0
HOH
W
173
1.334
4.996
−4.827
1.00
43.01
ATOM
3103
OW0
HOH
W
174
6.478
14.054
−35.398
1.00
65.54
ATOM
3104
OW0
HOH
W
175
−12.962
4.523
−16.881
1.00
54.38
ATOM
3105
OW0
HOH
W
176
8.991
14.162
−32.740
1.00
48.50
ATOM
3106
OW0
HOH
W
177
30.119
7.742
6.505
1.00
52.79
ATOM
3107
OW0
HOH
W
178
4.020
0.076
−9.889
1.00
58.79
ATOM
3108
OW0
HOH
W
179
1.144
5.559
−8.474
1.00
65.45
ATOM
3109
OW0
HOH
W
180
2.468
19.016
−2.946
1.00
58.33
ATOM
3110
OW0
HOH
W
181
8.790
31.553
−20.525
1.00
54.64
ATOM
3111
OW0
HOH
W
182
−2.088
20.162
20.999
1.00
50.34
ATOM
3112
OW0
HOH
W
183
−13.986
18.401
1.898
1.00
42.05
ATOM
3113
OW0
HOH
W
184
−12.269
28.571
−31.407
1.00
56.39
ATOM
3114
OW0
HOH
W
185
3.689
19.990
−5.623
1.00
51.48
ATOM
3115
OW0
HOH
W
186
−17.974
38.675
31.865
1.00
38.99
ATOM
3116
OW0
HOH
W
187
−19.158
28.362
36.510
1.00
54.63
ATOM
3117
OW0
HOH
W
188
−0.990
2.141
−5.489
1.00
52.92
ATOM
3118
OW0
HOH
W
189
−16.508
19.586
−9.105
1.00
39.50
ATOM
3119
OW0
HOH
W
190
−8.651
33.293
29.448
1.00
51.21
ATOM
3120
OW0
HOH
W
191
−21.074
18.375
−10.228
1.00
59.13
ATOM
3121
OW0
HOH
W
192
−6.961
2.168
−15.223
1.00
50.82
END
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Expert Influenza A Virus Vaccines and Inhibitors
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