# Patent

## Title
Crystal structure of liganded cFMS kinase domain

## Abstract

A crystal structure of the cfms kinase domain, co-crystal structure with a bound small molecule, as well as methods of using the same in the discovery of cfms inhibitors and in the treatment of diseases mediated by inappropriate cfms activity.

## Background
This application is a divisional of U.S. Ser. No. 10/391,416 filed on Mar. 18, 2003 now abandoned, which claims the benefit of U.S. Provisional Application No. 60/365,363 filed Mar. 18, 2002.


BACKGROUND OF THE INVENTION
The present invention relates to the crystal structure of the cfms kinase domain, specifically the cFMS kinase domain in liganded form, methods of using the same in the discovery of cFMS inhibitors and in the treatment of diseases mediated by inappropriate cfms activity, as well as diamino-pyrimidine cFMS inhibitors.
Colony stimulating factor-1 receptor (CSF-1R or CFMS), encoded by the proto oncogene c-fms (Sherr 1985; Woolford 1985), is a cell surface receptor for the macrophage colony-stimulating factor (M-CSF or CSF-1) and a member of the receptor tyrosine kinase (RTK) family of growth factor receptors. CSF-1 (or M-CSF) is a homodimeric growth factor involved in the proliferation, differentiation, and activation of monocytes or macrophages, as well as a proinflammatory cytokine (Tushinski 1982; Metcalf 1986; Becker 1987; Elliott 1989; Young 1990).
cFMS is a hematopoietic growth factor receptor, whose expression is lineage-specific and primarily confined to monocytes, macrophages and their bone marrow progenitors. cFMS is the cellular counterpart of the v-fms oncogene encoded by the genomes of both Susan McDonough and Hardy-Zuckerman five strains of feline sarcoma virus (Coussens 1986; Sherr 1988). The receptor is comprised of an extracellular ligand-binding domain joined through a single membrane-spanning helix to an intracellular protein tyrosine kinase (PTK) domain. It is closely related structurally to the receptors for the platelet-derived growth factor (PDGF), the stem cell factor receptor (the c-kit proto-oncogene product), and flt3/flt2. The extracellular ligand binding domain of these receptors is composed of five immunoglobulin-like loops (Wang 1993), and the PTK domains contain kinase insert (KI) sequences of varying lengths (Sherr, 1991). Binding of CSF-1 to the receptor extracellular ligand-binding domain causes a conformational change and induces a noncovalent dimerization of cFMS, autophosphorylation and activation of the PTK domain, and trans-phosphorylation of specific tyrosine residues in the cytoplasmic domain. These phosphorylated tyrosine residues serve as binding sites for src-homology 2 (SH2) domains contained within cytoplasmic signaling proteins (Sengupta 1988; Reedijk 1992), thereby activating signaling cascades. Both the PI3K-dependent and Ras/mitogen-activated protein kinase-dependent pathways are activated in response to CSF-1 binding to cFMS (Yeung 1998; Kelley, 1999; Kanagasundaram 1999). Following activation of cFMS with CSF-1, the receptor is rapidly internalized via clathrin-coated pits and vesicles and targeted to the lysosome for degradation.
cFMS receptor expression in macrophage populations corresponds to its stage of differentiation and tissue localization. CSF-1/cFMS interaction and signaling is required for the recruitment, development, and maintenance of a subset of macrophages, such as marrow and blood monocytes. Thus, an absence of cFMS is not life-threatening. Deletion of CSF-1, as occurs in the mutant mouse strain op/op and in the mutant rat strain th1/th1, provides an insight into the biology of cFMS/CSF-1 signaling. The op/op mutation renders an osteopetrotic phenotype with severely deficient macrophage populations in the joints, osteoclasts, peritoneal cavity phagocytes, splenic marginal zone metallophils, and lymph node subcapsular sinus macrophages. Other populations reach substantial levels, including bone marrow, phagocytes in the thymic cortex, splenic red pulp, lymph node medulla, intestinal lamina propria, liver (Kupffer cells), lung (alveolar macrophages), and brain (microglia) (Yoshida, H 1990; Wiktor-Jedrzejczak, W. 1991).
Connective tissue macrophages are involved in a number of chronic disease states, such as osteoarthritis, rheumatoid arthritis, osteoporosis, cardiovascular/vessel-wall disease, chronic graft rejection, Alzheimer's, and Lupus-nephritis (Yang 2001; Bischof, 2000; Boyce 1999; Cenci 2000; Campbell 2000; Murphy 2000). These macrophages directly or indirectly influence the production of disease modifiers (MMPs, cathepsins, chemokines, growth and differentiation factors) within the microenvironment (Valledor 2000).
Endogenous CSF-1 critically regulates HIV-1 replication in human monocyte-derived macrophages (MDM). The HIV-1 infected MDM cells produce high levels of CSF-1 by a mechanism that requires active virus replication. This aids the survival of infected macrophages and enhances the spread of infection by increasing macrophage susceptibility to the HIV virus. This suggests that CSF-1 might be a therapeutic target to block HIV-1 replication in human macrophages (Kalter 1991; Bergamini 1994; Gallo 1994; Kutza 2000).
Cancer studies have revealed elevated levels of circulating CSF-1 in patients with acute myeloid leukemia (AML) (Haran-Ghera 1997). It has also been reported that CSF-1 gene transduction into human lung carcinoma cell lines resulted in inhibition of metastic disease to the liver and lymph nodes, but not to the kidney. This suggests that the heterogeneity of organ microenvironments influences the spread of lung carcinoma (Yano 1997). Other evidence suggests that c-Fms activation by CSF-1 induces invasive disease by a urokinase-dependent pathway in breast carcinoma and neoplasms of the female reproductive tract (Kacinski 1997).
Inhibition of the c-fms receptor kinase represents a novel approach in the treatment of chronic disease by modulating proliferation, activation, differentiation, and migration of specific subpopulations of macrophages. It is envisioned that such a treatment would lead to a disease modifying effect—thereby alleviating signs and symptoms. Immunocompetence may be less compromised by this approach than by a more global inflammatory mediator depletion or immune suppressive approaches. Determination of a crystal structure of the cFMS kinase domain would provide a useful tool for indentifying ihibitors of cFMS.
The present inventors have determined the crystal structure of the cFMS kinase domain (cFMSK) alone and complexed with a cFMS inhibitor to 2.7 and 1.8 Å resolution, respectively. The crystal structure contains the non-phosphorylated, catalytic core as well as an N-terminal, juxtamembrane region (NT region). Such a crystal structure is useful in discovering compounds suitable for inhibiting cFMS and for treating diseases characterized by aberrant cfms activity. Also included in the present invention are diamino-pyrimidine cfms inhibitors.
BRIEF SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a cFMS kinase domain in liganded crystalline form, comprising the amino acid sequence of SEQ ID NO: 1 or 2 and having the structural coordinates of Table 2.
In a second aspect of the present invention, there is provided a method of CFMS inhibitor design, comprising:
generating a three dimensional computer model which represents a cFMS kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO: 1 or 2 and having the structural coordinates of Table 2;
evaluating compounds as potential cFMS inhibitors using said model; and
selecting compounds for further testing based on said evaluation.
In a third aspect of the present invention, there is provided a method of cFMS inhibitor design, comprising:
generating a three dimensional computer model which represents a cFMS kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO: 1 or 2 and having the structural coordinates of Table 2;
evaluating compounds as potential cFMS inhibitors using said model; wherein said evaluation comprises identifying compounds capable of at least one of the following cFMS kinase domain/compound interactions:
(i) one or more interactions with amino acid residues of the CFMS kinase domain hinge region;
(ii) one or more interactions with amino acid residues of the CFMS kinase domain adenine pocket,
(iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
(iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
(v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface; and
selecting compounds for further testing based on said evaluation.
In a fourth aspect of the present invention, there is provided a method of cFMS inhibitor design, comprising:
generating a three dimensional computer model which represents a cFMS kinase domain in liganded form, said kinase domain described by the amino acid sequence of SEQ ID NO: 1 or 2 and having the structural coordinates of Table 2;
evaluating compounds as potential cFMS inhibitors using said model; wherein said evaluation comprises identifying compounds capable of at least one of the following cFMS kinase domain/compound interactions:
(i) one or more interactions with amino acid residues 663, 664, 665, 666, 667, 668, and 669;
(ii) one or more interactions with amino acid residues 588, 614, 647, and 785,
(iii) one or more interactions with amino acid residues 596 and 797 and/or one or more hydrogen bonding interactions with amino acid residue residue 796,
(iv) one or more interactions with amino acid residues 550, 640, 646, 769, and 776, and
(v) one or more interactions with residues 668 and 672; and
selecting compounds for further testing based on said evaluation.
In a fifth aspect of the present invention, there is provided a method of treating a disorder characterized by inappropriate cFMS activity in a mammal, comprising: administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cfms kinase domain thereby resulting in a cFMS kinase domain in liganded form, said kinase domain in liganded form being described by the amino acid sequence of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2, wherein said complex is characterized by at least one of the following cfms kinase domain/compound interactions:
(i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
(ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
(iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
(iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
(v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface.
In a sixth aspect of the present invention, there is provided a method of inhibiting cFMS in a mammal, comprising: administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cfms kinase domain thereby resulting in a cFMS kinase domain in liganded form, said kinase domain in liganded form being described by the amino acid sequence of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2, wherein said complex is characterized by at least one of the following cfms kinase domain/compound interactions:
(i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
(ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
(iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
(iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
(v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface.
In a seventh aspect of the present invention, there is provided a compound of formula (I):




or a salt, solvate, or physiologically functional derivative thereof:

    wherein
    R1 is —H or C1-C6 alkyl;
    R2 is —H, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, or —(CH2)p R6;
    n is 1 or 2;
    p is 1, 2, or 3;
    R3 is —H or C1-C6 alkoxy;
    R4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, -halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, —SR5, or n is 2 and each R4 together with the phenyl ring to which they are attached form the group






    R5 is C1-C6 alkyl; and
    R6 is NR5R5, heterocyclyl, aryl, or heteroaryl.





BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a ribbon representation, prepared with RIBBONS, of apo cFMSK.
FIG. 2 depicts a representation of the various regions of the ATP binding site of cFMSK.
FIG. 3 depicts a representation, created with QUANTA, of the binding of a diamino inhibitor of formula (I) to the ATP binding site of cFMSK.
FIG. 4 depicts a superposition, prepared with QUANTA, of the NT region and A-loops in the cFMSK apo and inhibitor structures.
FIG. 5 depicts the various rings (A, B, and C) and nitrogens (1, 2, and 3) of the compound of formula 1(a).



DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein the term “cFMS” refers to the colony stimulating factor-1 receptor and the term “cFMSK” refers to the colony stimulating factor-1 kinase domain. It is also understood that unless otherwise indicated both terms include within its scope both unactivated and activated forms. That is, the phosphorylated and unphosphorylated forms.
As used herein, the term “mutation” carries its traditional connotation and means a change, inherited, naturally occurring or introduced, in a nucleic acid or polypeptide sequence, and is used in its sense as generally known to those of skill in the art.
As used herein, the term “labeled” means the attachment of a moiety, capable of detection by spectroscopic, radiologic or other methods, to a probe molecule.
As used herein, the term “target cell” refers to a cell, into which it is desired to insert a nucleic acid sequence or polypeptide, or to otherwise effect a modification from conditions known to be standard in the unmodified cell. A nucleic acid sequence introduced into a target cell can be of variable length. Additionally, a nucleic acid sequence can enter a target cell as a component of a plasmid or other vector or as a naked sequence.
As used herein, the term “transcription” means a cellular process involving the interaction of an RNA polymerase with a gene that directs the expression as RNA of the structural information present in the coding sequences of the gene. The process includes, but is not limited to, the following steps: (a) the transcription initiation, (b) transcript elongation, (c) transcript splicing, (d) transcript capping, (e) transcript termination, (f) transcript polyadenylation, (g) nuclear export of the transcript, (h) transcript editing, and (i) stabilizing the transcript.
As used herein, the term “expression” generally refers to the cellular processes by which a biologically active polypeptide is produced from RNA.
As used herein, the term “transcription factor” means a cytoplasmic or nuclear protein which binds to a gene, or binds to an RNA transcript of such gene, or binds to another protein which binds to such gene or such RNA transcript or another protein which in turn binds to such gene or such RNA transcript, so as to thereby modulate expression of the gene. Such modulation can additionally be achieved by other mechanisms; the essence of “transcription factor for a gene” is that the level of transcription of the gene is altered in some way.
As used herein, the term “hybridization” means the binding of a probe molecule, a molecule to which a detectable moiety has been bound, to a target sample.
As used herein, the term “detecting” means confirming the presence of a target entity by observing the occurrence of a detectable signal, such as a radiologic or spectroscopic signal that will appear exclusively in the presence of the target entity.
As used herein, the term “sequencing” means determining the ordered linear sequence of nucleic acids or amino acids of a DNA or protein target sample, using conventional manual or automated laboratory techniques.
As used herein, the term “isolated” means oligonucleotides substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which they can be associated, such association being either in cellular material or in a synthesis medium. The term can also be applied to polypeptides, in which case the polypeptide will be substantially free of nucleic acids, carbohydrates, lipids and other undesired polypeptides.
As used herein, the term “substantially pure” means that the polynucleotide or polypeptide is substantially free of the sequences and molecules with which it is associated in its natural state, and those molecules used in the isolation procedure. The term “substantially free” means that the sample is at least 50%, preferably at least 70%, more preferably 80% and most preferably 90% free of the materials and compounds with which is it associated in nature.
As used herein, the term “primer” means a sequence comprising two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and more preferably more than eight and most preferably at least about 20 nucleotides of an exonic or intronic region. Such oligonucleotides are preferably between ten and thirty bases in length.
As used herein, the term “DNA segment” means a DNA molecule that has been isolated free of total genomic DNA of a particular species. For example, a DNA segment encoding a cFMS or cFMSK polypeptide refers to a DNA segment that encodes SEQ ID NO: 1 or SEQ ID NO: 2, i.e., SEQ ID NO: 3 and SEQ ID NO: 4 respectively, yet is isolated away from, or purified free from, total genomic DNA of a source species, such as Homo sapiens. Included within the term “DNA segment” are DNA segments and smaller fragments of such segments, and also recombinant vectors, including, for example, plasmids, cosmids, phages, viruses, and the like.
As used herein, the phrase “enhancer-promoter” means a composite unit that contains both enhancer and promoter elements. An enhancer-promoter is operatively linked to a coding sequence that encodes at least one gene product.
As used herein, the phrase “operatively linked” means that an enhancer-promoter is connected to a coding sequence in such a way that the transcription of that coding sequence is controlled and regulated by that enhancer-promoter. Techniques for operatively linking an enhancer-promoter to a coding sequence are well known in the art; the precise orientation and location relative to a coding sequence of interest is dependent, inter alia, upon the specific nature of the enhancer-promoter.
As used herein, the term “inhibitor candidate” means a substance that is believed to interact with another moiety, for example a given ligand that is believed to interact to at least partially inhibit the activity of a complete cFMS or cFMS polypeptide, or fragment thereof, and which can be subsequently evaluated for such an interaction and activity inhibition. Representative candidate compounds or substrates include xenobiotics such as drugs and other therapeutic agents, carcinogens and environmental pollutants, natural products and extracts, as well as endobiotics such as steroids, fatty acids and prostaglandins. Other examples of candidate substances that can be investigated using the methods of the present invention include, but are not restricted to, agonists and antagonists of a cFMS or cFMSK polypeptide, toxins and venoms, viral epitopes, hormones (e.g., opioid peptides, steroids, etc.), hormone receptors, peptides, enzymes, enzyme substrates, co-factors, lectins, sugars, oligonucleotides or nucleic acids, oligosaccharides, proteins, small molecules and monoclonal antibodies.
As used herein, the term “modified” means an alteration from an entity's normally occurring state. An entity can be modified by removing discrete chemical units or by adding discrete chemical units. The term “modified” encompasses detectable labels as well as those entities added as aids in purification.
As used herein, the term “interaction” means any relationship between atoms or molecules whereby atomic and/or molecular conditions or forces exist which promote binding equilibrium between such atoms or molecules. Suitable examples include, but are not limited to electrostatic, hydrophobic, hydrophilic, hydrogen, and van der Waals bonding. The nature of such bonding relationships is known in the art and is described for instance in Mathews et al (1990) Biochemistry, Chapter 2, pgs 30-54.
As used herein, the terms “structure coordinates” and “structural coordinates” are interchangeable and mean mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) of a cFMSK molecule in crystal form. The diffraction data are used to calculate an electron density map of the repeating unit of the crystal. The electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.
Those of skill in the art understand that a set of structure coordinates determined by X-ray crystallography is not without standard error. For the purpose of this invention, any set of structure coordinates for cFMSK or a cFMSK mutant that have a root mean square (RMS) deviation from ideal of no more than 1.5 Å, when superimposed using the polypeptide backbone atoms on the structure coordinates listed in Table 2, shall be considered identical, except that for the activation loop and nucleotide binding loop such deviation from ideal have a RMS of no more than 10 Å.
As used herein, the term “asymmetric unit” means part of a symmetric object from which the whole is built up by repeats. Thus, it is the smallest unit from which the object can be generated by the symmetry operations of its point group.
As used herein, the term “molecular replacement” means a method that involves generating a preliminary model of cFMS or cFMSK mutant crystal whose structure coordinates are unknown, by orienting and positioning a molecule whose structure coordinates are known within the unit cell of the unknown crystal so as best to account for the observed diffraction pattern of the unknown crystal. Phases can then be calculated from this model and combined with the observed amplitudes to give an approximate Fourier synthesis of the structure whose coordinates are unknown. This, in turn, can be subject to any of the several forms of refinement to provide a final, accurate structure of the unknown crystal (Lattman, (1985) in Methods in Enzymology, 115: 55-77). Using the structure coordinates of cFMSK and cFMSK in liganded form provided by this invention, molecular replacement can be used to determine the structure coordinates of a crystalline mutant or homologue of cFMSK or of a different crystal form of cFMSK.
As used herein, the terms “β-sheet” and “beta sheet” are interchangeable and mean the conformation of a polypeptide chain stretched into an extended zig-zig conformation. Portions of polypeptide chains that run “parallel” all run in the same direction. Polypeptide chains that are “antiparallel” run in the opposite direction from the parallel chains.
As used herein, the terms “α-helix” and “alpha helix” are interchangeable and mean the conformation of a polypeptide chain wherein the polypeptide backbone is wound around the long axis of the molecule in a left-handed or right-handed direction. The substituent groups of the amino acids protrude outward from the helical backbone, wherein the repeating unit of the structure is a single turn of the helix, which extends about 0.56 nm along the long axis.
As used herein, the term “mutant” means a polypeptide which is obtained by replacing at least one amino acid residue in a native cFMS or cFMSK polypeptide with a different amino acid residue and/or by adding and/or deleting amino acid residues within the native polypeptide or at the N- and/or C-terminus of a polypeptide corresponding to a native cFMS or cFMSK and which has substantially the same three-dimensional structure as the native cFMS or cFMSK from which it is derived. By having substantially the same three-dimensional structure is meant having a set of atomic structure coordinates that have a root mean square deviation (RMS deviation) of less than or equal to about 1.5 Å, (10 Å for the activation loop and nucleotide binding loop) when superimposed with the atomic structure coordinates of the native cFMS or cFMSK from which the mutant is derived when at least about 50% to 100% of the Cα atoms of the native cFMS or cFMSK are included in the superposition. A mutant can have, but need not have, autophosphorylation activity.
As used herein, the term “space group” means a group or array of operations consistent with an infinitely extended regularly repeating pattern. It is the symmetry of a three-dimensional structure, or the arrangement of symmetry elements of a crystal. There are 230 space group symmetries possible; however, there are only 65 space group symmetries available for biological structures.
As used herein, the term “symmetry” means some spatial manipulation of an object resulting in an indistinguishable object. A symmetric object can, therefore, be superimposed on itself by some operation.
As used herein, the term “unit cell” means the fundamental portion of a crystal structure that is repeated infinitely by translation in three dimensions. A unit cell is characterized by three vectors a, b, and c, not located in one plane, which form the edges of a parallelepiped. Angles α, β and γ define the angles between the vectors: angle α is the angle between vectors b and c; angle β is the angle between vectors a and c; and angle γ is the angle between vectors a and b. The entire volume of a crystal can be constructed by regular assembly of unit cells; each unit cell comprises a complete representation of the unit of pattern, the repetition of which builds up the crystal.
As used herein, “monoclinic unit cell” means a unit cell wherein a≠b≠c and α=γ=90° and β≠90°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles.
As used herein, “orthorhombic unit cell” means a unit cell wherein a≠b≠c; and α=β=γ=90°. The vectors a, b and c describe the unit cell edges and the angles α, β, and γ describe the unit cell angles.
As used herein, the term “crystal lattice” means the array of points defined by the vertices of packed unit cells.
As used herein, the term “active site” means that site in the cFMSK domain where substrate peptide binding, ATP binding and catalysis occur. For cFMS, the active site comprises at least the activation loop and the nucleotide binding loop.
As used herein, the term “activation loop” refers to a loop in tyrosine kinase domains between the conserved AspPheGly sequence and the conserved AlaProGlu sequence that is believed to act as a regulatory loop.
As used herein the terms “nucleotide-binding loop” and “glycine-rich loop” are synonomous and mean a loop in an RTK which contains the protein kinase-conserved glycine-rich consensus sequence.
As used herein, the term “autophosphorylation site” means a residue or residues in cFMSK that is phosphorylated by a domain of cFMS itself.
As used herein the term “juxtamembrane region” means that portion of cFMSK located between the transmembrane helix and the tyrosine kinase domain.
As used herein, the terms “kinase insert” and “kinase insert domain” are synonymous and mean an additional domain not found in non-receptor tyrosine kinases or serine/threonine kinases. It is found between helices αD and αE in the C-terminal domain of receptor tyrosine kinases and can vary greatly in sequence and length.
As used herein, the term “C-terminal tail” means that region of an RTK that extends beyond the final helix of the C-terminal domain of the RTK.
As used herein, the term “N-terminal domain” means that region of an RTK that has a defined structure and precedes in sequence the hinge region.
As used herein, the term “modulate” means an increase, decrease, or other alteration of any or all chemical and biological activities or properties of a wild-type or mutant cFMS or cFMSK polypeptide.
As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein the term “alkyl” refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aryl, aryloxy, heteroaryl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo, or C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
As used herein, the term “C1-C6 alkyl” refers to an alkyl group, as defined above, containing at least 1 and at most 6 carbon atoms respectively. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, and n-hexyl.
As used herein, the term “alkylene” refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo and C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
As used herein, the term “C1-C3 alkylene” refers to an alkylene group, as defined above, which contains at least 1, and at most 3, carbon atoms respectively. Examples of “C1-C3 alkylene” groups useful in the present invention include, but are not limited to, methylene, ethylene, and n-propylene.
As used herein, the term “alkenyl” refers to a hydrocarbon radical having from two to ten carbons and at least one carbon-carbon double bond, optionally substituted with substituents selected from the group which includes C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halo and C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkenyl” as used herein include, ethenyl, propenyl, 1-butenyl, 2-butenyl, and isobutenyl.
As used herein, the term “C1-C6 alkenyl” refers to an alkenyl group as defined above containing at least 1, and at most 6, carbon atoms. Examples of “C1-C6 alkyl” groups useful in the present invention include, but are not limited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, and isobutenyl.
As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen radicals fluoro (—F), chloro (—Cl), bromo (—Br), and iodo (—I).
As used herein, the term “C1-C6 haloalkyl” refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms respectively substituted with at least one halo group, halo being as defined herein. Examples of such branched or straight chained haloalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halos, e.g., fluoro, chloro, bromo and iodo.
As used herein, the term “C1-C6 hydroxyalkyl” refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms respectively substituted with at least one hydroxy group, hydroxy being as defined herein. Examples of such branched or straight chained hydroxyalkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more hydroxy groups.
As used herein, the term “cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring. In a like manner the term “C3-C7 cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms and which optionally includes a C1-C6 alkyl linker through which it may be attached. The C1-C6 alkyl group is as defined above. Exemplary “C3-C7 cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a three to twelve-membered non-aromatic heterocyclic ring, being saturated or having one or more degrees of unsaturation, containing one or more heteroatom substitutions selected from S, S(O), S(O)2, O, or N, optionally substituted with substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, aryl, heteroaryl, heterocyclyl, nitro, cyano, halo, or C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more other “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” moieties include, but are not limited to, tetrahydrofuran, pyranyl, 1,4-dioxanyl, 1,3-dioxanyl, piperidinyl, piperazinyl, 2,4-piperazinedionyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, and the like.
As used herein, the term “aryl” refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or napthalene ring systems. Exemplary optional substituents include C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino optionally substituted by alkyl or acyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aryl, or heteroaryl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, heteroaryl, heterocyclyl, aryl, ureido, arylurea, alkylurea, cycloalkylurea, alkylthiourea, aryloxy, or aralkoxy, multiple degrees of substitution being allowed. Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substituted derivatives thereof.
As used herein, the term “aralkyl” refers to an aryl or heteroaryl group, as defined herein, attached through a C1-C3 alkylene linker, wherein the C1-C3 alkylene is as defined herein. Examples of “aralkyl” include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl, 3-isoxazolylmethyl, and 2-imidazoyly ethyl.
As used herein, the term “heteroaryl” refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic or tricyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members selected from a group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C1-C6 perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of “heteroaryl” groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, and substituted versions thereof.
As used herein, the term “alkoxy” refers to the group RaO—, where Ra is alkyl as defined above and the term “C1-C6 alkoxy” refers to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms. Exemplary C1-C6 alkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
As used herein, the term “hydroxy” refers to the group —OH.
As used herein, the term “amino” refers to the group —NH2.
As used herein the term “alkylamino” refers to the group —NHRa wherein Ra is alkyl as defined above.
As used herein the term “arylamino” refers to the group —NHRa wherein Ra is aryl as defined above.
As used herein the term “aralkylamino” refers to the group —NHRa wherein Ra is an aralkyl group as defined above.
As used herein the term “aralkoxy” refers to the group RbRaO—, where Ra is alkylene and Rb is aryl or heteroaryl all as defined above.
As used herein the term “aryloxy” refers to the group RaO—, where Ra is aryl or heteroaryl both as defined above.
As used herein the term “ureido” refers to the group —NHC(O)NH2 .
As used herein, the term “arylurea” refers to the group —NHC(O)NHRa wherein Ra is aryl as defined above.
As used herein, the term “arylthiourea” refers to the group —NHC(S)NHRa wherein Ra is aryl as defined above.
As used herein, the term “alkylurea” refers to the group —NHC(O)NHRa wherein Ra is alkyl as defined above.
As used herein, the term “cycloalkylurea” refers to the group —NHC(O)NHRa wherein Ra is cycloalkyl as defined above.
As used herein, the term “haloalkoxy” refers to the group RaO—, where Ra is haloalkyl as defined above and the term “C1-C6 haloalkoxy” refers to a haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1, and at most 6, carbon atoms. Exemplary C1-C6 haloalkoxy groups useful in the present invention include, but is not limited to, trifluoromethoxy.
As used herein, the term “alkylsulfanyl” refers to the group RaS—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfanyl” refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
As used herein, the term “alkylsulfenyl” refers to the group RaS(O)—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfenyl” refers to an alkylsulfenyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
As used herein, the term “alkylsulfonyl” refers to the group RaS(O)2—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfonyl” refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
As used herein, the term “alkylsulfonylamino” refers to the group —NHS(O)2Ra wherein Ra is alkyl as defined above and the term “C1-C6 alkylsulfonylamino” refers to an alkylsulfonylamino group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
As used herein, the term “arylsulfonylamino” refers to the group —NHS(O)2Ra wherein Ra is aryl as defined above.
As used herein, the term “alkylcarboxyamide” refers to the group —NHC(O)Ra wherein Ra is alkyl, amino, or amino substituted with alkyl, aryl or heteroaryl as described above.
As used herein the term “alkylcarboxy” refers to the group —C(O)Ra wherein Ra is alkyl as described above.
As used herein, the term “oxo” refers to the group ═O.
As used herein, the term “mercapto” refers to the group —SH.
As used herein, the term “carboxy” refers to the group —C(O)OH.
As used herein, the term “cyano” refers to the group —CN.
As used herein the term “cyanoalkyl” refers to the group —CNRa, wherein Ra is alkyl as defined above. Exemplary “cyanoalkyl” groups useful in the present invention include, but are not limited to, cyanomethyl, cyanoethyl, and cyanoisopropyl.
As used herein, the term “aminosulfonyl” refers to the group —S(O)2NH2.
As used herein, the term “carbamoyl” refers to the group —C(O)NH2.
As used herein, the term “sulfanyl” shall refer to the group —S—.
As used herein, the term “sulfenyl” shall refer to the group —S(O)—.
As used herein, the term “sulfonyl” shall refer to the group —S(O)2— or —SO2—.
As used herein, the term “acyl” refers to the group RaC(O)—, where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
As used herein, the term “aroyl” refers to the group RaC(O)—, where Ra is aryl as defined herein.
As used herein, the term “aroylamino” refers to the group RaC(O)NH—, where Ra is aryl as defined herein.
As used herein, the term “heteroaroyl” refers to the group RaC(O)—, where Ra is heteroaryl as defined herein.
As used herein, the term “alkoxycarbonyl” refers to the group RaOC(O)—, where Ra is alkyl as defined herein.
As used herein, the term “acyloxy” refers to the group RaC(O)O—, where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
As used herein, the term “aroyloxy” refers to the group RaC(O)O—, where Ra is aryl as defined herein.
As used herein, the term “heteroaroyloxy” refers to the group RaC(O)O—, where Ra is heteroaryl as defined herein.
As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
As used herein, the term “physiologically functional derivative” refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the compounds of formula (I) are included within the scope of the compounds of formula (I).
Description of APO cFMSK Structure
The overall architecture of cFMSK was analogous to structures reported previously for both serine/threonine and tyrosine protein kinases (Mohammadi 1996 and McTigue 1999). A Cαtrace of cFMSK is shown in FIG. 1, where kinase secondary structural elements are labeled according to the convention originally given for cAPK (Knighton & Sowadski, 1991). cFMSK folds into two domains, with catalysis occurring in a cleft between the two domains. Residues in the N-terminal domain are primarily responsible for ligating ATP, while residues in the C-terminal domain are involved in catalysis and substrate binding.
The N-terminal domain (residues 575-669) folds into a twisted β-sheet and one α-helix. The larger C-terminal domain (residues 670-919) contains seven α-helices (αD-αI) and two sets of anti-parallel β-strands (β7/β8 and β9/β10). Strands 7 and 8 are positioned at the interdomain interface adjacent to the N-terminal β-sheet. Like other kinases, cFMSK also contains functionally important loop regions: the glycine-rich nucleotide binding loop (residues 590-594), the catalytic loop (residues 776-783) and the activation loop (residues 796-825), which are described in further detail below.
Activation Loop
Protein kinases contain a large flexible loop, called the activation loop or A-loop, whose conformation is believed to regulate kinase activity. In many kinases, the conformation of the A-loop is controlled by the phosphorylation of specific residues within this region (Johnson 1996). The activation loop generally begins with a conserved AspPheGly sequence (cFMSK 796) and ends at a conserved AlaProGlu (cFMSK 825). In structures of inactive kinases, this loop often blocks either the substrate or ATP binding sites (Hubbard 1994; Mohammadi 1996; and McTigue 1999).
Upon phosphorylation, the A-loop is repositioned to contact residues in the C-terminal domain (Hubbard 1997). The activating phosphate can then interact with a cluster of basic residues, which includes a conserved arginine (cFMSK R777), that precedes the catalytic aspartate (cFMSK D778). The aspartyl residue of the AspPheGly motif ligates a Mg2+ ion, which, in turn contacts the β and γ phosphates of ATP.
In cFMSK, the activation loop corresponds to residues 796-825 and contains a single tyrosine at position 809. In the apo cFMSK structure presented here, the A-loop folds under the nucleotide binding loop, partially blocking both the ATP and substrate binding sites. The Phe of the conserved AspPheGly motif sits in the ATP binding site and the side chain of cFMSK Phe797 overlays with the ribose of ATP and packs under Val596. Arg801 occupies the beta and gamma phosphate binding site. The carbonyl oxygen of Asp796 forms a hydrogen bond with the epsilon amino group of the catalytic Lys616. Leu799 packs deep into the back of the ATP binding site, packing under the nucleotide binding loop and displacing it upwards relative to its position observed in other kinase structures (Hubbard 1994; Hubburd 1997; Mohammadi 1996; and McYigue 1999).
Nucleotide Binding Loop
The nucleotide binding loop (NB loop) contains residues responsible for binding the triphosphate moiety of ATP in the correct position for catalysis (Johnson 1996 and Cox 1994). This glycine-rich loop is believed to be quite flexible and is often either disordered or has high b-factors in many unliganded kinase structures (Mohammadi 1996 and McTigue 1999). In cFMSK, this loop is well defined and packs against residues in the A-loop. Leu799 of the activation loop, packs deep into the back of the ATP binding site, displacing the NB loop upwards relative to its position observed in other kinase structures (Hubbard 1994; Hubburd 1997; Mohammadi 1996; and McTigue 1999).
Juxtamembrane Region
The cFMSK constructs contains 32 additional residues preceding the conserved catalytic core (residues 542-574). In the apo and inhibitor complex structures, 18 and 28 of these residues are well defined, respectively. In the apo structure, a loop within this region is disordered (residues 555-563). While the function of this juxtamembrane region is unclear, previous studies with murine cFMS suggest that Tyr559 (human Tyr561), is phosphorylated in vivo and interacts with the SH2 domain of Fyn (Alonso 1995). Mutation of this residue to alanine, in the murine protein, eliminates rapid ligand-induced endocytosis of receptor molecules and lose of kinase activity [Myles 1994]. In v-cfms, Tyr544 (human Tyr546) is phosphorylated and interacts with an unidentified 55 kDa protein (Joos 1996). In both the apo and inhibitor complex structures, the NT region is located in close proximity to the ATP binding site. In the inhibitor structure, Tyr561 is located on a solvent exposed loop. The structural or conformational consequences of phosphorylating this residue are not clear.
Catalytic Loop
The catalytic loop of protein kinases lies between αE and β7 and contains an invariant aspartic acid (D778 in cFMS) that serves as the catalytic base in the phosphotransfer reaction (Johnson 1996). The sequence in cFMS is HRDVAARN (residues 776-783). In cFMSK, the backbone and side chain positions of this loop are similar to those in the unliganded FGFR1, Tie2, IRK and VEGFR2 and in the ternary phosphorylated IRK complex structures (Hubbard 1994; Mohammadi 1996; McTigue 1999; and Shewchuk 2000).
Kinase Insert Domain (KID)
Many RTKs contain an insert of variable length and sequence between αD and αE in their C-terminal domain. This insert can be as short as 12 or as long as 97 residues, as in IRK and the platelet-derived growth factor receptor β (PDGFRβ), respectively (Hubbard 1994 and Heideran 1991). Deletion or mutation of this region in other kinases revealed that the KID is not necessary for intrinsic kinase activity (McTigue 1999; Heideran 1991; and Taylor 1989). However, this kinase insert domain may be important for protein-protein interactions involved in signal transduction via phosphorylation of KID residues (Heideran 1991 and Taylor 1989). In cFMS, this region corresponds to residues 668-750 and contains 3 tyrosine, 10 serine and 2 threonine residues. Previous studies with murine cFMS suggested that 3 tyrosine residues within the KID (murine Tyr697, 706 and 721; human Tyr699, 708, 723) were phosphorylated in response to CSF-1 binding to the extracellular domain. Phosphorylated Tyr697, in the murine protein, associates with Grb2, enabling the nucleotide exchange factor Sos1 to activate Ras. Phosphorylated Tyr706 is involved in activation of the STAT1 transcription factor while phosphorylated Tyr721 binds the regulatory p85 subunit of PI-3 kinase. In addition, previous mutational studies suggested that the cFMS KID targets the protein for degradation, following internalization (Carlberg 1991).
The early constructs utilized, that contained the KID, were heterogeneously phosphorylated on 3 serines within the KID (Ser688, Ser713 and Ser733) and yielded poorly diffracting crystals. Therefore, the KID was deleted for structural studies. In both deletion constructs, residues surrounding the deletion were disordered in the crystal structure (residues 687-746). Interestingly helix D, leading into the KID, is nearly twice as long in cFMS than in FGFR1 and VEGFR2.
ATP Binding Site
The ATP binding site (see FIG. 2) can be broken down into several regions: hinge, adenine pocket, sugar pocket, phosphate region, back hydrophobic pocket and solvent interface. ATP is modeled into cfms based on the activated IR structure. The hinge region runs from thr663 to cys667 and would be expected to form hydrogen bonds with the adenine base of ATP. In the orientation shown in the figure, the adenine pocket would be formed by leu588 and ala614 on top, leu785 on the bottom, val647 in the back, and the hinge region on the left side. The sugar pocket would have val596 on top and gly795 on the bottom. The phosphate region would contain gly795, asp796, phe797, arg782, and asn783 on the bottom and right side, and lys616 and glu633 on top. The hydrophobic back pocket in cfms would be formed by thr663, met637, leu640, ile646, leu769, trp550, and his776. A surface at the solvent interface formed by residues gly668 to asn672 could form both hydrophobic and hydrophilic interactions with inhibitors.
Inhibitor/cFMSK Complex Structure
The structure of nonphosphorylated cFMSK was also solved in the presence of a compound of formula (I):




or a salt, solvate, or physiologically functional derivative thereof:

    wherein
    R1 is —H or C1-C6 alkyl;
    R2 is —H, C1-C6 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, or —(CH2)p R6;
    n is 1 or 2;
    p is 1, 2, or 3;
    R3 is —H or C1-C6 alkoxy;
    R4 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkoxy, -halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, aryl, —SR5, or n is 2 and each R4 together with the phenyl ring to which they are attached form the group






    R5 is C1-C6 alkyl; and
    R6 is NR5R5, heterocyclyl, aryl, or heteroaryl.


Specifically, the structure of nonphosphorylated cFMSK was also solved in the presence of a diamino pyrimidine inhibitor of formula (I):
(pIC50=7.5, Formula (Ia)).




The protein-inhibitor complex was co-crystallized under different conditions and in a different space group then the apo protein (Table 1). While the overall fold was the same for the apo and inhibitor complex structures, differences were observed in the A-loop and NT region.

The diamino pyrimidine group hydrogen bonds to the hinge region between the N and C-terminal domains (See FIG. 3). In FIG. 3, the inhibitor is highlighted in bolded lines and the hydrogen bonding is indicated with dashed lines. N1 and N2 (see FIG. 5) of the inhibitor hydrogen bond to the carbonyl and main chain NH of Cys666, respectively. N3 forms a bidentate hydrogen bond to the carbonyl of Glu664 and side chain of Thr663. The B and C rings (see FIG. 5) of the inhibitor lie deep in the back of the ATP binding site, in a pocket not present in the apo structure. The 2 ether oxygens hydrogen bond to the main chain NH of Asp796. The B ring packs against Val647, while the C ring sits in a hydrophobic pocket formed by Ile646, Met637, Leu640, Leu769, Trp550, and H776.
Both the activation loop and NT region move to accommodate inhibitor binding (FIG. 4). In the inhibitor complex structure, the entire NT region is ordered. Residues 546-551 of the NT region, form the back of the inhibitor binding pocket and shift to accommodate the C ring of the inhibitor. Trp 550 makes an edge-to-face interaction with the inhibitor C ring. The end of the inhibitor, corresponding to the C ring of the cFMSK inhibitor, is solvent exposed.
The A-loop in the inhibitor complex is still in an inactive, inhibitory conformation. The first 6 residues of the A-loop shift, relative to their position in the apo structure, to accommodate inhibitor binding. Specifically, Phe797 moves out of the ATP binding site.
While the inhibitor binds to the inactive, nonphosphorylated form of cFMSK in the crystal structure, it presumably also binds to the active, phosphorylated form of the protein. Nonphosphorylated cFMSK will autophosphorylate itself in vitro on Tyr809 in the A-loop, increasing kinase activity  ̃10 fold. Similar IC50s were observed for the inhibitor on cFMSK whether the inhibitor was added before or after preincubation with ATP in an in vitro kinase assay.
Co-crystal structures were also solved using each of the following diaminopyrimidine compounds of formula (Ib), (Ic), and (Id) of the present invention.




As recited above, the present invention provides a cFMS kinase domain in liganded crystalline form. Such cFMS liganded kinase domain is described by the amino acid sequence of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2. In one embodiment, the SEQ ID is SEQ ID NO: 1. In an alternative embodiment, the SEQ ID is SEQ ID NO: 2. SEQ ID NO: 1 is encoded by the DNA sequence of SEQ ID NO: 3 and SEQ ID NO: 2 is encoded by the DNA sequence of SEQ ID NO: 4. In a further embodiment, is a substantially pure and isolated cFMS kinase domain in liganded crystalline form described by the amino acid sequence of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2. In one embodiment, the SEQ ID is SEQ ID NO: 1. In an alternative embodiment, the SEQ ID is SEQ ID NO: 2.
In one embodiment the liganded cFMS kinase domain in crystalline form has lattice constants of a=80 Å, b=80 Å, c=78 Å, α=90°, β=90°, and γ=90°. In one embodiment, the liganded cFMS kinase domain in crystalline form has a space group of R3. In another embodiment, the liganded cFMS kinase in crystalline form has an entire NT region which is ordered. In still another embodiment, the liganded cFMS kinase in crystalline form has structural coordinates having a deviation from ideal with a RMS of no more than 1.5 Å except that the activation loop and/or a nucleotide binding loop have structural coordinates having a deviation from ideal with a RMS of no more than 10 Å. In a further embodiment, the liganded cFMS kinase in crystalline form has an activation loop and/or a nucleotide binding loop have structural coordinates having a deviation from ideal with a RMS of no more than 10 Å.
In another embodiment, there is provided a cFMS kinase domain/inhibitor complex which includes a cFMS liganded kinase domain described by the amino acid sequence of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2 and a compound capable of at least one of the following interactions with the cFMS kinase domain:
(i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
(ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
(iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
(iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
(v) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface;
preferably
(i) one or more interactions with amino acid residues 663, 664, 665, 666, 667, 668, and 669;
(ii) one or more interactions with amino acid residues 588, 614, 647, and 785,
(iii) one or more interactions with amino acid residues 596 and 797 and/or one or more interactions with amino acid residue 796,
(iv) one or more interactions with amino acid residues 550, 640, 646, 769, and 776, and
(v) one or more interactions with residues 668 and 672.
More preferred embodiments of interactions (i), (ii), (iii), (iv), and (v) are described following.
The amino acid region referred to in the interactions described in (i), which include amino acid residues 663-669, is typically referred to as the hinge region (see FIG. 2). In one embodiment, there are one or more kinase domain/compound hydrogen bonding interactions with at least one of amino acid residues 663 to 669, preferably two or more hydrogen bonding interactions with at least one of amino acid residues 663 to 669, more preferably three or more hydrogen bonding interactions with at least one of amino acid residues 663 to 669, most preferably four or more hydrogen bonding interactions with at least one of amino acid residues 663 to 669.
In one embodiment, there is a kinase domain/compound hydrogen bonding interaction with threonine 663, preferably one hydrogen bonding interaction with the side chain oxygen of threonine 663. Typically, this hydrogen bond is at a distance of 2.7 to 3.7, preferably 2.9 to 3.5, more preferably 3.1 to 3.3 Å. In another embodiment, there is a kinase domain/compound hydrogen bonding interaction with glutamic acid 664, preferably one hydrogen bonding interaction with a carbonyl oxygen of glutamic acid 664. Typically, this hydrogen bond is at a distance of 2.3 to 3.3, preferably 2.5 to 3.1, more preferably 2.7 to 2.9 Å. In another embodiment, there is a kinase domain/compound hydrogen bonding interaction with cysteine 666, preferably one hydrogen bonding interaction with the carbonyl oxygen of cysteine 666. Typically, this hydrogen bond is at a distance of 2.3 to 3.3, preferably 2.5 to 3.1, more preferably 2.7 to 2.9 Å. In a further embodiment, there is one kinase domain/compound hydrogen bonding interaction with the backbone —N(H)— of cysteine 666. Typically, this hydrogen bond is at a distance of 2.8 to 3.8, preferably 3.0 to 3.6, more preferably 3.2 to 3.4 Å. In one embodiment, there are two kinase domain/compound hydrogen bonding interactions with cysteine 666, preferably one hydrogen bonding interaction with the carbonyl oxygen and one hydrogen bonding interaction with the backbone —N(H)— of cysteine 666.
In a more preferred embodiment, there is one kinase domain/compound hydrogen bonding interaction with each of threonine 663 and glutamic acid 664 and two hydrogen bonding interactions with cysteine 666. In a most preferred embodiment, there are four kinase domain/compound hydrogen bonding interactions: (i) a hydrogen bonding interaction with the side chain oxygen of threonine 663, (ii) a hydrogen bonding interaction with the carbonyl oxygen of glutamic acid 664, (iii) a hydrogen bonding interaction with the carbonyl oxygen of cysteine 666, and (iv) a hydrogen bonding interaction with the backbone —N(H)— of cysteine 666.
The amino acid region referred to in the interactions in (ii) described what is commonly termed the adenine pocket (see FIG. 2), which is formed by residues 588 and 614 on top, residue 785 on the bottom, and residue 647 in the back, with the hinge region, described above, being on the left side of the pocket. In one embodiment, there are one or more kinase domain/compound hydrophobic interactions with at least one of amino acid residues 588, 614, 647, and 785, preferably two or more hydrophobic interactions with at least two of amino acid residues 588, 614, 647, and 785, more preferably three or more hydrophobic interactions with at least three of amino acid residues 588, 614, 647, and 785, most preferably four or more hydrophobic bonding interactions with at least four of amino acid residues 588, 614, 647, and 785.
In one embodiment, there is a kinase domain/compound hydrophobic interaction with leucine 588, preferably a hydrophobic interaction with the side chain of leucine 588. In another embodiment, there is a kinase domain/compound hydrophobic interaction with alanine 614, preferably a hydrophobic bonding interaction with the side chain of alanine 614. In another embodiment, there is a kinase domain/compound hydrophobic interaction with valine 647, preferably a hydrophobic interaction with the side chain of valine 647. In a further embodiment, there is a kinase domain/compound hydrophobic interaction with leucine 785, preferably a hydrogen bonding interaction with the side chain of leucine 785.
In a more preferred embodiment, there is one kinase domain/compound hydrophobic interaction with each of leucine 588, alanine 614, valine 647, and leucine 785. In a most preferred embodiment, there are four kinase domain/compound hydrophobic bonding interactions: (i) a hydrophobic interaction with the side chain of leucine 588, (ii) a hydrophobic interaction with the side chain of alanine 614, (iii) a hydrophobic interaction with the side chain of valine 647, and (iv) a hydrophobic interaction with the side chain of leucine 785.
The amino acid region referred to in the interactions in (iii) described what is commonly termed the sugar pocket (see FIG. 2), which is formed by residue 596 on top and residue 795 on the bottom and the phosphate region formed by residues 795, 796, 797, 782 and 783 on the bottom and right side and residues 616 and 633 on top. In one embodiment, there are one or more kinase domain/compound hydrophobic interactions with at least one of amino acid residues 596 and 797 and one or more hydrogen bonding interactions with residue 796, preferably two or more hydrophobic interactions with amino acid residues 596 and 797 and two hydrogen bonding interactions with residue 796.
In one embodiment, there is a kinase domain/compound hydrophobic interaction with valine 596, preferably a hydrophobic interaction with the side chain of valine 596. In another embodiment, there is a kinase domain/compound hydrophobic interaction with phenylalanine 797, preferably a hydrophobic interaction with the side chain of phenylalanine 797. In one embodiment, there is one, preferably two hydrogen bonding interactions with aspartic acid 796.
In a more preferred embodiment, there is one kinase domain/compound hydrophobic interaction with each of valine 596 and phenylalanine 797. In a most preferred embodiment, there are two kinase domain/compound hydrophobic bonding interactions: (i) a hydrophobic interaction with the side chain of valine 596 and (ii) a hydrophobic interaction with the side chain of phenylalanine 797, and two hydrogen bonding interactions with the backbone —N(H)— of aspartic acid 796. Typically, one of these hydrogen bonds is at a distance of 2.7 to 3.7, preferably 2.9 to 3.5, more preferably 3.1 to 3.3 Å and the other hydrogen bond is at a distance of 2.2 to 3.2, preferably 2.4 to 3.1, more preferably 3.6 to 2.8 Å.
The amino acid region referred to in the interactions in (iv) described what is commonly termed the back pocket (see FIG. 2), which is formed by residues 663, 637, 640, 646, 769, 550, and 776. In one embodiment, there are one or more kinase domain/compound hydrophobic interactions with at least one of amino acid residues 637, 640, 646, 663, 769, and 776, preferably two or more hydrophobic interactions with at least two of amino acid residues 637, 640, 646, 663, 769, and 776, more preferably three or more hydrophobic interactions with at least three of amino acid residues 637, 640, 646, 663, 769, and 776, still more preferably four or more hydrophobic bonding interactions with at least four of amino acid residues 637, 640, 646, 663, 769, and 776, even more preferably five or more hydrophobic bonding interactions with at least four of amino acid residues 637, 640, 646, 663, 769, and 776, and most preferably six or more hydrophobic bonding interactions with at least four of amino acid residues 637, 640, 646, 663, 769, and 776.
In one embodiment, there is a kinase domain/compound hydrophobic interaction with methionine 637, preferably a hydrophobic interaction with the side chain of methionine 637. In another embodiment, there is a kinase domain/compound hydrophobic interaction with leucine 640, preferably a hydrophobic bonding interaction with the side chain of leucine 640. In another embodiment, there is a kinase domain/compound hydrophobic interaction with isoleucine 646, preferably a hydrophobic interaction with the side chain of isoleucine 646. In a further embodiment, there is a kinase domain/compound hydrophobic interaction with threonine 663, preferably a hydrophobic interaction with the side chain of threonine 663. In another further embodiment, there is a kinase domain/compound hydrophobic interaction with leucine 769, preferably a hydrophobic interaction with the side chain of leucine 769. In another embodiment, there is a kinase domain/compound hydrophobic interaction with histidine 776, preferably a hydrophobic interaction with the side chain of histidine 776.
In a more preferred embodiment, there is one kinase domain/compound hydrophobic interaction with each of methionine 637, leucine 640, isoleucine 646, threonine 663, leucine 769, and histidine 776. In a most preferred embodiment, there are six kinase domain/compound hydrophobic bonding interactions: (i) a hydrophobic interaction with the side chain of methionine 637, (ii) a hydrophobic interaction with the side chain of leucine 640, (iii) a hydrophobic interaction with the side chain of isoleucine 646, (iv) a hydrophobic interaction with the side chain of threonine 663, (v) a hydrophobic interaction with the side chain of leucine 769, and (vi) a hydrophobic interaction with the side chain of histidine 776.
The amino acid region referred to in the interactions in (v) describe what is commonly termed the solvent interface (see FIG. 2), which is formed by residues 668 and 672. In one embodiment, there are one or more kinase domain/compound hydrophobic and/or hydrophilic interactions with at least one of amino acid residues 668 and 672, preferably two or more hydrophobic and or hydrophilic interactions with at least two of amino acid residues 668 and 672, more preferably three or more hydrophobic and/or hydrophilic interactions with at least two of amino acid residues 668 and 672.
In one embodiment, there is a kinase domain/compound hydrophobic and/or hydrophilic interaction with glycine 668. In another embodiment, there is a kinase domain/compound hydrophobic and/or hydrophilic interaction with asparagine 672.
In a more preferred embodiment, there is one kinase domain/compound hydrophobic and/or hydrophilic interaction with each of glycine 668 and asparagine 672. In a most preferred embodiment, there are two kinase domain/compound hydrophobic and/or hydrophilic interactions: (i) a hydrophobic and/or hydrophilic interaction with glycine 668 and (ii) a hydrophobic and/or hydrophilic interaction with asparagine 672.
In another embodiment, residues 546-551 of the NT region of the cfms kinase domain shift to accommodate the compound.
In one embodiment, the compound is a compound of formula (I) a, b, c, or d.
The method of cFMS inhibitor design of the present invention includes as a first step: generating a three dimensional computer model which represents a cFMS kinase domain in liganded form, said kinase domain being described by the amino acid sequence of SEQ ID NO: 1 or 2 and having the structural coordinates of Table 2. Typically, such a computer model of SEQ ID NO: 1 or 2 and the structural coordinates of Table 2 is constructed utilizing a commercially available software program. Software programs for generating three-dimensional graphical representations of molecules or portions thereof from a set of structural coordinates are well known and used in the art. Suitable examples of such computer programs for viewing or otherwise manipulating protein structures include, but are not limited to, the following: Midas (University of California, San Francisco), MidasPlus (University of California, San Francisco), MOIL (Univeristy of Illinois), Yummie (Yale University), Sybyl (Tripos, Inc.), Insight/Discover (Biosym Technologies), MacroModel (Columbia University), Quanta (Molecular Simulations, Inc.), CNS (Molecular Simulations, Inc.), Cerius (Molucular Simulations, Inc.), Alchemy (Tripos, Inc.), LabVision (Tripos, Inc.), Rasmol (Glaxo Research and Development), Ribbon (University of Alabama), NAOMI (Oxford University), Explorer Eyechem (Silicon Graphics, Inc.), Univision (Cray Research), Molscript (Uppsala University), Chem-3D (Cambridge Scientific), Chain (Baylor College of Medicine), O (Uppsala University), GRASP (Columbia University), X-Plor (Molecular Simulations, Inc., Yale University), Spartan (Wavefunction, Inc.), Catalyst (Molecular Simulations, Inc.), Molcadd (Tripos, Inc.), VMD (University of Illinois/Beckman Institute), Sculpt (Interactive Simulations, Inc.), Procheck (Brookhaven National Laboratory), DGEOM (QCPE), RE_VIEW (Brunel University), Modeller (Birbeck College, University of London), Xmol (Minnesota Supercomputing Center), Protein Expert (Cambridge Scientific), HyperChem (Hypercube), MD Display (University of Washington), PKB (National Center for Biotechnology Information, NIH), ChemX (Chemical Design, Ltd.), Cameleon (Oxford Molecular, Inc.), and Iditis (Oxford Molecular, Inc.).
Once the three dimensional model of the cFMS kinase domain is established candidate inhibitor compounds may be evaluated utilizing the model and the selected software application. Initially, it is understood that the term “evaluate” includes within its scope, without limitation, de novo inhibitor molecular design, computer-aided optimization of known candidate inhibitors, as well as computer-based selection of candidate inhibitors. Various computational analysis methods are known in the art for the evaluation of potential binding interactions between a polypeptide binding pocket and a candidate inhibitor molecule. Such methods typically utilize at least one of the software packages recited above and are known in the art. Computational and other evaluation methods are described for instance in U.S. Pat. Nos. 6,251,620 and 6,356,845, such patents being incorporated herein by reference to the extent that they disclose computational and other evaluation methods for drug design, selection and/or optimization.
Examples of protein-inhibitor interactions which are screened for include potential electrostatic, hydrophobic, hydrophilic, van der Waals, and hydrogen bonding between the cFMS kinase molecule and candidate inhibitors as well as favorable candidate inhibitor conformations within the cFMS kinase binding pocket.
In one embodiment, evaluation of compounds as potential cFMS inhibitors using said model comprises identifying compounds capable of at least one of the following cFMS kinase domain/compound interactions:
(i) one or more interactions with amino acid residues of the cFMS kinase domain hinge region;
(ii) one or more interactions with amino acid residues of the cFMS kinase domain adenine pocket,
(iii) one or more interactions with amino acid residues of the cFMS kinase sugar pocket and phosphate region,
(iv) one or more interactions with amino acid residues of the cFMS kinase domain back pocket, and
(vi) one or more interactions with amino acid residues of the cFMS kinase domain solvent interface;
preferably
(i) one or more interactions with amino acid residues 663, 664, 665, 666, 667, 668, and 669;
(ii) one or more interactions with amino acid residues 588, 614, 647, and 785,
(iii) one or more interactions with amino acid residues 596 and 797 and/or one or more interactions with amino acid residue residue 796,
(iv) one or more interactions with amino acid residues 550, 640, 646, 769, and 776, and
(v) one or more interactions with residues 668 and 672.
Further preferred embodiments of the interactions (i), (ii), (iii), (iv), and (v) are as described above.
If evaluation indicates that a compound shows promise as a candidate inhibitor the compounds are selected for further testing based on said evaluation. An inhibitor candidate is generally sought which can exist in a conformation which appears to be structurally compatible with at least a part of the cFMS kinase domain binding pocket. Such conformation will be sterically and energetically compatible with the cFMS kinase domain. Typically, the above listed non-covalent or secondary bonding interactions will be important in the interaction of the candidate inhibitor and the cFMS kinase domain. In addition, other conformational factors include the overall three dimensional structure and orientation of the candidate inhibitor within the protein structure, especially the binding pocket as well as spatial and energetic relationships of the various functional groups of the candidate inhibitor and cFMS kinase domain which have potential for interaction. The further testing done typically is to evaluate the inhibitory effect on the kinase activity of cFMS and may take the form of enzyme or cell based assays as well as other assays known in the art for measuring the inhibitory effect on the kinase activity of cFMS.
The present invention also provides a method of inhibiting cFMS in a mammal, which includes administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cFMS kinase domain thereby resulting in a cfms kinase domain in liganded form. Also provided is a method of treating a disorder characterized by inappropriate cFMS activity in a mammal which includes administering to said mammal a therapeutically effective amount of a compound that can form a complex with a cFMS kinase domain thereby resulting in a cFMS kinase domain in liganded form.
Compounds useful in the treatment methods of the present invention include those having interactions (i), (ii), (iii), (iv), and (v) with the cFMS kinase domain. Such interactions are as described above.
The inappropriate cFMS activity referred to herein is any cFMS activity that deviates from the normal cFMS activity expected in a particular mammalian subject. Inappropriate cFMS activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of cFMS activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Furthermore, it is also understood that unwanted cFMS activity may reside in an abnormal source, such as a malignancy. That is, the level of cFMS activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
While it is possible that, for use in therapy, therapeutically effective amounts of the compounds described in the present invention, as well as salts, solvates and physiologically functional derivatives thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of the compounds described herein and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (Ia, b, c, d) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the present invention or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the present invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the present invention, and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The compounds of the present invention and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of the present invention per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
EXAMPLES
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.
Structure Determination
Initial attempts to crystallize the catalytic core of cFMS (cFMSK) were unsuccessful due to poor expression and solubility of the protein. Limited proteolysis and mass spectroscopic analysis of the entire cytoplasmic region suggested the kinase insert domain (KID) was heterogeneously phosphorylated and not well folded and that the NT region may provide stability. Two new constructs were made based on these studies with different sized deletions of the KID. Construct 1 contained residues 542-919Δ696-741, while construct 2 contains 542-919Δ682-741. Both constructs also contain a 6-histidine tag at the N-terminus for purification purposes. Constructs were expressed in baculovirus-infected insect cells and purified by standard chromatographic procedures. Crystallization screens were initially performed using non-phosphorylated protein alone or complexed with a diaminopyrimidine inhibitor. Three different crystal forms of apo cFMSK were obtained: crystal forms I and II using construct 1 and crystal form III with construct 2 (Table 1). The protein inhibitor complex, using either construct 1 or 2, yielded crystal form IV.
The structure of crystal form I was solved by molecular replacement using the structure of the of fibroblast growth factor receptor 1 (FGFR1) catalytic core (Mohammadi 1996) as a search model. The structure was refined to an R-factor of 20% at 2.7 Å resolution. 5 residues at the N-terminus, 3 residues at the C-terminus and a loop within the NT region (residues 555-563) were disordered and could not be modeled. 16 residues surrounding the kinase insert domain deletion were also disordered (residues 687-696 and 741-746). The structures of crystal forms II and IV were solved by molecular replacement using the structure determined for crystal form I. The structure in crystal form III was not fully refined due to the poor quality of the data and large number of molecules in the asymmetric unit. The overall fold in crystal forms I, II and IV was essentially identical, however significant differences in the activation loop and NT region were observed between the apo and inhibitor complex structures.
Certain embodiments of the present invention will now be illustrated by way of example only.
Materials and Methods
Construct Generation
A combination of limited proteolysis and modeling was used to define the constructs for structural studies. First, the cytoplasmic domain of cFMS was cloned from a human universal library (Clontech, Palo Alto, Calif.) by PCR. The sequence was identical to that reported in GENBANK (X03663). The coding region corresponding to residues 538-972 was fused to a 6×His tag (MKKGHHHHHHG) and subcloned into a pFASTBAC1 (Gibco BRL) expression vector by PCR (construct 1). The N-terminal primer included an EcoRI restriction. The C-terminal primer included a stop codon and a SphI restriction site. The cfms construct was transfected into Spodoptera frugiperda (sf-9) cells, single plaques were isolated, and high titer stocks were generated. Construct A was expressed and purified, as described below for the final truncated constructs.
Limited proteolysis was performed on construct A to define a smaller, stable catalytic domain (see below for more details). Proteolysis suggested that both the N- and C-terminus could be truncated and that the kinase insert domain was not well ordered. Therefore, a second construct (construct B) was generated corresponding to residues 542-919 fused to a 6× his tag (MKKGHHHHHHG). The protein was expressed and purified as described below for the final constructs.
Construct B did not yield suitable crystals. Peptide mapping of a tryptic digest of construct 2, by mass spectrometry, indicated that 3 serines were heterogeneously phosphorylated (688, 713 and 733). A third construct (construct C) was generated in which the serines at position 688, 713 and 733 were mutated to alanine, using the following 3 primers—5′ggacccagcctggcccccggccaggac 3′, 5′ gtccgcagggacgctggcttctccagc 3′, 5′gtctccacttctgcaaatgactccttc 3′. This construct also did not yield suitable crystals.
Two final constructs, 1 and 2, were generated with the same his tag and N and C termini as construct B and C but with different length deletions of the kinase insert domain. Deletions were designed by modeling the kinase domain of cfms using the Tie2, FGFR1, IRK and VEGFR2 crystal structures. Residues 696-741 and 682-741 were deleted in constructs 1 and 2 respectively. The proteins were expressed, purified and crystallized as described below.
Limited Proteolysis
Purified construct A was digested with a panel of 8 proteases in a 96 well plate. 5 ug of cFMS (5 uL at 1 mg/mL) was added to 5 uL of 10 mg/mL protease in 20 uL of reaction buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl). Reactions were stopped at 0.75, 2, and 18 hours with 10 uL of 4×SDS-PAGE sample buffer. All digests were analyzed by SDS-PAGE (NuPAGE Novex 10% Bis-Tris gel, MES running buffer). Bands of interest were electroblotted on PVDF membrane and subjected to Edman sequencing.















Source (Boehringer Mannheim



Proteases used
unless otherwise noted)









1.) Trypsin
catalogue # 1418475



2.) Chymotrypsin
catalogue # 1418467



3.) Lys C
catalogue # 1047825



4.) Glu C
catalogue # 1047817



5.) Asp N
catalogue # 1054589



6.) Arg C
catalogue # 1370529



7.) Thermolysin
catalogue # 161586



8.) Subtilisin
catalogue # 572908 (Calbiochem)










Protein Fermentation/Purification

Four constructs were generated for structural studies. The fermentation and purification was similar for all constructs.
Fermentation: Large-scale (2L) virus preparations for fermentation were made by infecting Sf-9 cells growing in Grace's Supplemented medium (GIBCO/Life Technologies)+0.1% capluronic® F-68 (GIBCO/Life Technologies)+10% FBS (HyClone Laboratories) at a multiplicity of infection (MOI) of 0.1 in 6L shake flasks at 27.5° C. and 120 RPM. Viral supernatants were harvested at 72 hours post-infection via centrifugation at 2500 RPM for 20 minutes. Viral titers were determined via ELISA. A 36 L stirred bioreactor (University Research Glassware) was outfitted with external overhead stirrer & water bath and internal dip tubes, heat-transfer coil, paddle-style impeller and dO2 probe. The bioreactor was inoculated with Trichoplusia ni(T. ni) cells [kindly obtained from JRH BioSciences (Woodland, Calif.)] at  ̃0.5×106/mL. The culture was grown in Ex-CellTM 405 insect cell medium (JRH BioSciences)+50 μg/mL gentamicin (GIBCO/Life Technologies). The temperature was maintained at 27.5° C. using an external water bath, an internal temperature probe and heat-transfer coil. Agitation was maintained at 30 RPM using an external overhead drive and an internal paddle-type impeller. Dissolved oxygen was maintained at 50% via sparging under the control of an internal dO2 probe. Cells were allowed to double overnight at the above parameters, and the culture was then infected at a density of  ̃1×106/mL at MOI=1. The culture was monitored daily for pH, glucose, lactate and glutamine levels as well as cell count and viability via trypan blue exclusion. Infection was allowed to proceed at the above parameters, and cells were harvested at 48 hours post-infection using a Centritech® 100 continuous flow centrifuge (DuPont). Concentrated cells were subsequently centrifuged at 2000 RPM for 20 minutes and washed with protease inhibitor buffer [1× Dulbecco's PBS (GIBCO/Life Technologies), 1 mM EDTA (Sigma), 1 mM p-aminobenzamidine (Sigma), 1 μg/mL aprotinin (Boehringer Mannheim), 1 μg/mL leupeptin (Boehringer Mannheim)]. Cells were centrifuged again at 2000 RPM for 20 minutes. The supernatant was decanted, and the cells were flash frozen in a dry ice/ethanol bath and stored at −80° C. until further purification.

Purification: All operations were carried out at 4° C. 12 L of T. ni cells (220 g of wet cell pellet stored −80° C.) was thawed in 1500 mL of lysis buffer. The cells were suspended using a polytron homogenizer twice for 60 seconds each time. The homogenate was centrifuged for 40 minutes at 30,000×g (14,000 rpm) in a Sorvall SLA 1500 rotor. The pelleted material was discarded, and the supernatant was filtered through a 1.2 micron cartridge filter. The lysate was directly loaded onto the first column.

1st Column Step: A 2.6 cm diameter column was packed with a Amersham Pharmacia Ni-Chelating Sepharose FF resin to a 65 mL bed volume. The Chelating Sepharose resin was coupled at a 30 μmol Ni/mL gel (complete Ni/gel saturation). A BioPilot instrument (Amersham Pharmacia) was used as the liquid chromotography operating system and was run at a 20 mL/minute flow rate. Before sample loading, the column was equilibrated with 5 column volumes (CV's) of Ni-Chelating buffer A. After sample loading, the column was washed for 5 CV's with Ni-Chelating buffer A. A non-linear gradient was applied to the column with a 5 CV step, 13% Ni-Chelating buffer B wash step, followed by a 5 CV gradient to 100% Ni-Chelating buffer B. 25 mL fractions were collected. The fractions containing cFMS protein (major absorbance peak after the 13% Ni-Chelating buffer B wash step) were pooled together (200 mL) and EDTA and DTT were added to a final concentration of 1 mM. The pool was diluted to a final volume of 800 mL using Ni-pool dilution buffer. The 800 mL pool was loaded directly onto the next column.

2nd Column Step: A 2.6 cm diameter column was packed with a Poros HS (Perceptive) cation exchange resin to a 40 mL bed volume. A BioPilot instrument was used as the LC operating system and was run at a 25 mL/minute flow rate. After loading the 800 mL Ni-Chelating pool, the column was washed with cation buffer A for 5 CV. The column was step eluted with a series of increasing 100 mM NaCl steps. A single fraction was collected during the 300 mM NaCl step. The 300 mM NaCl cation eluate was concentrated using a 10,000 KDa molecular weight cut off (MWCO) membrane to a final volume of 12 mL. The concentrated retentate was directly loaded onto the next column.

3rd Column Step: Size exclusion chromatography. The retentate was loaded onto a pre-packed S-75 Superdex size exclusion column (Amersham Pharmacia XK 2.6 column, 320 mL CV). The operating system was a FPLC (Amersham Pharmacia) instrument that was run at a 3 mL/minute flow rate. 4 mL fractions were collected. The fractions from the top 75-80% of the major peak eluting from the column were combined into a single pool. The pool was concentrated using a 10K MWCO membrane to a final volume of 9 mL.

Buffers:

    1. Ni-Chelating buffer A: 25 mM HEPES (pH 7), 200 mM NaCl, 40 mM imidazole.
    2. Ni-Chelating buffer B: 25 mM HEPES (pH 7), 200 mM NaCl, 400 mM imidazole.
    3. Ni-pool dilution buffer: 20 mM HEPES (pH 7), 1 mM DTT, 1 mM EDTA, 5% (v/v) glycerol.
    4. Cation buffer A: 25 mM HEPES (pH 7), 1 mM DTT.
    5. Cation buffer B: 25 mM HEPES (pH 7), 1 mM DTT, 1000 mM NaCl.
    6. SEC buffer: 20 mM HEPES (pH 7), 100 mM NaCl, 5 mM DTT.

Protein Digestion for Mass Spectrometry



Trypsin digestions of 200-1000 picomoles of cFMS were carried out in 50 mM Tris pH 8.5, 1 mM CaCl2, and 10% acetonitrile. In some instances, cFMS was reduced and alkylated with DTT and 4-vinylpyridine prior to digestion. Digestion proceeded at 37° C. for 12-18 hours.
Mass Spectrometry: LCMS
Mass measurements of intact protein were determined using liquid chromatography mass spectrometry (LCMS). Protein samples were initially desalted on a Poros R2/H column (Perceptive Biosystems; Framingham, Mass.). Effluent from the desalting column was directed to a SCIEX API III mass spectrometer (PE Sciex, Concord, ON, Canada), and spectra were acquired in positive ion mode with electrospray ionization. Intact protein mass values were obtained from the reconstructed mass spectra that were generated from the processed data. Assignment of phosphorylation states were made by identifying masses that were multiples of 80 Da higher than the expected mass of cFMS.
Mass Spectrometry: nanoES MS
Nanoelectrospray ionization (nanoES) MS on a Q-TOF instrument from Micromass (UK) was used to map phosphorylation sites after trypsin digestion. Sample was introduced to the MS with either static nanoES using a pulled capillary tip (Mann) or capillary LCMS/MS. The LC system was from LC Packings and consisted of the Famos autosampler and the Ultimate solvent delivery pump. Separation was carried out on a 75 μm I.D. C.18 PepMap column (LC Packings). The Q-TOF is capable of data dependent ion selection for collision induced fragmentation.
Two sample preparation approaches were used to map the phosphorylation sites. In the first approach, phosphorylated peptides were isolated from non-phosphorylated peptides using Ga(III) immobilized metal affinity chromatography (IMAC). Briefly, an aliquot of the trypsin digest was acidified and loaded onto an IMAC microcolumn charged with Ga(III). The column was then washed with 0.1% acetic acid/30% acetonitrile to remove non-phosphorylated peptides. Retained peptides were then eluted with 0.2 M sodium phosphate, pH 8.2 and directly applied to a microcolumn packed with Poros R2/H reverse phase media. Bound peptides were washed with 0.1% formic acid and then eluted directly into a nanoelectrospray capillary tip. Static nanoESI was used to acquire MS and MS/MS spectra of the purified peptides. Phosphorylated residues were identified from MS/MS data.
In the second approach, the cFMS trypsin digest was analyzed by capillary LCMS/MS with data dependant scanning. This data file was then used to conduct a Mascot protein database search that compared uninterpreted MS/MS data to theoretical MS/MS spectra of user specified proteolytic peptides. The spectra were interpreted manually to confirm the assignment.
Preparation of Inhibitor Candidate Compounds
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
















g (grams);
mg (milligrams);



L (liters);
mL (milliliters);



μL (microliters);
psi (pounds per square inch);



M (molar);
mM (millimolar);



mol (moles);
mmol (millimoles);










All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.
1H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, a Brucker AVANCE-400, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
HPLC were recorded on a Gilson HPLC or Shimazu HPLC system by the following conditions. Column: 50×4.6 mm (id) stainless steel packed with 5 μm Phenomenex Luna C-18; Flow rate: 2.0 mL/min; Mobile phase: A phase=50 mM ammonium acetate (pH 7.4), B phase=acetonitrile, 0-0.5 min (A: 100%, B: 0%), 0.5-3.0 min (A:100-0%, B:0-100%), 3.0-3.5 min (A: 0%, B: 100%), 3.5-3.7 min (A: 0-100%, B: 100-0%), 3.7-4.5 min (A: 100%, B: 0%); Detection:UV 254 nm; Injection volume: 3 μL.
Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; LC-MS were recorded on a micromass 2MD and Waters 2690; high resolution MS were obtained using a JOEL SX-102A spectrometer. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. Most of the reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
Compounds of Formula I can be prepared according to the synthetic sequences illustrated in Schemes 1-4 and further detailed in the Examples section following.
















Intermediate Example 1
3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}prop-2-enenitrile




To a homogeneous solution of 2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}-3-morpholin-4-ylprop-2-enenitrile (14.5 g, 36.7 mmol) in isopropanol (050 mL) was added aniline hydrochloride (4.9 g, 37.5 mmol), and the mixture was stirred at reflux for 20 minutes, combined with 20 mL of water and cooled in an ice bath for 30 minutes. The resulting precipitate was filtered off, washed with water and air dried to give 13.7 g of crude product. This material was recrystalized from methanol/ethanol to afford pure product as a crystalline tan solid (10.5 g, 26.2 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.03 (d, J=12.8 Hz, 1H), 7.59 (d, J=12.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.4 Hz, 2H), 7.16 (m,2H), 6.93 (d, J=8.2 Hz, 1H), 6.88 (d, J=8.4, 1H), 6.86 (m, 1H), 6.83 (s, 1H), 4.90 (s, 2H), 3.69 (s, 3H), 3.68 (s, 3H), 3.50 (s, 2H), 3.28 (s, 2H). MS (ES-, m/z)=399 (M−H).
Intermediate Example 2
2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}-3-morpholin-4-ylprop-2-enenitrile




3-Methoxy-4-[(4-methoxybenzyl)oxy]benzaldehyde (20.0 g, 73.4 mmol) and 3-morpholinopropronitrile (Lancaster, 11.0 g, 77.1 mmol) were stirred in DMSO (15 mL) at 65 C until the mixture was homogeneous. The solution was cooled to 40 C and sodium methoxide (0.79 g, 14.7 mmol) was added. The mixture was stirred at 75 C for 15 minutes, then cooled to room temperature and diluted with dichloromethane (150 mL) and water (200 mL). 1N HCl (25 mL) was added and the two layers were seperated. The organics were combined and dried (magnesium sulfate), filtered and concentrated to a red oil (29.5 g, 73 mmol) that was used directly in the synthesis of 3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}prop-2-enenitrile. 1H NMR (300 MHz, d6-DMSO): δ 7.38 (d, 2H), 7.03-6.95 (m,3H), 6.84 (t, J=13.5 Hz, 2H), 6.73 (d, J=8.2 Hz, 1H), 4.98 (s, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, 2H), 3.55-3.50 (m, 3H), 3.46-3.43 (m, 2H), 3.36 (s, 1H), 3.33-3.29 (m, 2H). MS (ES+, m/z)=395 (M+H).
Intermediate Example 3
3-Methoxy-4-[(4-methoxybenzyl)oxy]benzaldehyde




A mixture of 4-hydroxy-3-methoxybenzaldehyde (22.6 g, 149 mmol), 4-methoxybenzyl chloride (23.3 g, 149 mmol) and potassium carbonate (30.8 g, 223 mmol) was stirred in N,N-dimethylformamide (DMF) (150 mL) at 90 C for 2 hours. The solution was filtered hot, and cooled to room temperature. The filtrate was concentrated and dissolved ethyl acetate (300 mL) and extracted with aqueous sodium bicarbonate and water. The organics were dried with magnesium sulfate, filtered and concentrated. The crude product was recrystalized with ethyl acetate and hexanes to give product as an off-white solid (34.2 g, 126 mmol). 1H NMR (300 MHz, d6-DMSO): δ 9.86 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.44-7.40 (m, 3H), 7.30 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 5.15 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H). MS (ES+, m/z)=273 (M+H).
Intermediate Example 4
N-Phenyl-guanidine nitrate




To a solution of aniline (1.28 ml, 14 mmol) in ethanol (14 ml) was added cyanamide (1.25 ml, 16.1 mmol) and nitric acid (1 ml, 14 mmol), and the reaction was heated to reflux. After 16 hours, the reaction was cooled to room temperature and poured into diethyl ether. The resulting precipitate was filtered and dried to afford the title compound as a gray solid (2.50 g, 13 mmol, 90%). NMR (300 MHz, CD3OD): δ 7.47 (m, 2H), 7.36 (m, 1H), 7.30 (m, 2H).
Example 1
5-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}pyrimidine-2,4-diamine




A suspension of 3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl) oxy]benzyl}prop-2-enenitrile (300 mg, 0.75 mmol) and guanidine hydrochloride (108 mg, 1.13 mmol) in ethanol (5 mL) was stirred at room temperature while sodium methoxide was added. The mixture was stirred at reflux overnight. The solution was cooled 5 C and 2N sodium hydroxide (2 mL) was added. After 15 minutes, a white precipitate was filtered off and washed with water then hexane to give product as a white solid (199 mg, 0.54 mmol). 1H NMR (300 MHz, d6-DMSO): δ 7.45 (s, 1H), 7.32 (d, J=8.6 Hz, 2H), 6.93-6.85 (m, 4H), 6.66 (dd, J=8.3 and 1.5 Hz, 1H), 6.02 (s, 2H), 5.65 (s, 2H), 4.91 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 3.50 (s, 2H). MS (ES+, m/z)=367 (M+H).
Example 2
5-[3-Methoxy-4-(4-methoxy-benzyloxy)-benzyl]-N2-phenyl-pyrimidine-2,4-diamine




To a solution of 2,3-anilino-2-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}prop-2-enenitrile (400 mg, 1.0 mmol) and N-phenyl-guanidine nitrate (495 mg, 2.5 mmol) was added a solution of potassium tert-butoxide (1M, 7.5 mmol), and the reaction was heated at 80 C. After 72 hours, the reaction was cooled to room temperature and concentrated. The residue was dissolved in 10% MeOH/CH2Cl2 and passed through a plug of silica gel. The filtrate was concentrated and purified by column chromatography (50% EtOAc/Hexanes) to give the title compound as a yellow foam (172 mg, 0.39 mmol, 39%). 1H NMR (300 MHz, d6-DMSO): δ 8.86 (s, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.34 (d, J=8.7 Hz, 3H), 7.19 (t, J=7.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 4H), 6.83 (m, 1H), 6.71 (dd, J=8.1 and 1.8 Hz, 1H), 6.47 (br s, 2H), 4.93 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.60 (s, 2H). MS (ES+, m/z)=468 (M+H).
The following compounds of Examples 3-30 of Formula I′ were prepared according to the procedure of Schemes 1 and 2 and Example 1 and were characterized as being the indicated compound.












(I′)








 












Example
N
R4
Location*
















3
1
—Cl
Para



4
1
—F
Para



5
1
—OCH3
Para



6
1
—CF3
Para



7
1
—Br
Para



8
1
—CH3
Meta



9
1
—OCH3
Meta



10
1
—Cl
Meta



11
1
—CF3
Meta



12
1
—Br
Meta



13
2
—Cl, —Cl
Meta, Para



14
1
—OCF3
Para



15
1
—C(CH3)3
Para



16
1
—CH2CH3
Para



17
1
—CH(CH3)2
Para



18
1
—CH═CH2
Para



19
2
—Cl, —CH3
Meta, Para



20
2
—Br, —Br
Meta, Meta



21
2
—CH3, —CH3
Meta, Para



22
2
—F, —CH3
Meta, Para



23
2
—CH3, —F
Meta, Para



24
2
—CF3, —Cl
Meta, Para



25
2
—Cl, —OCF3
Meta, Para



 



26
1




Para



 



27
2
—Cl, —Cl
Ortho, Para



28
1
—I
Para



29
1
—SCH3
Para



 



30
2




Fused to Phenyl







*Location is in reference to the attachment to the CH2 group of the benzyloxy moiety.






The following compounds of Examples 31-56 of Formula I′′ were prepared according to the procedure of Schemes 1-4 and Examples 1 and 2 and were characterized as being the indicated compound.













(I′′)








 









Example
R1
R2





31
—H






 


32
—H
—(CH2)3N(CH3)2


 


33
—H






 


34
—H
—CH3


35
—H
—CH2CH3


36
—CH3
—CH3


 


37
—H






 


38
—H
—(CH2)3CH3


 


39
—H






 


40
—H






 


41
—H






 


42
—H






 


43
—H






 


44
—H






 


45
—H






 


46
—H






 


47
—H






 


48
—H






 


49
—H






 


50
—H






 


51
—H






 


52
—H






 


53
—H






 


54
—H






 


55
—H






 


56
—H
—CH(CH3)2









The following compounds of Examples 57-75 of Formula I′′′ were prepared according to the procedure of Schemes 1-4 and Examples 1 and 2 and were characterized as being the indicated compound.












(I′′′)








 











Example
R1
R2
R4
n and Location*





57
—H




—CF3
1: Para


 


58
—H




—CF3
1: Para


 


59
—H




—CF3
1: Para


 


60
—H




—C(CH3)3
1: Para


 


61
—H




—OCF3; —Cl
2: Para, Meta


 


62
—H




—C(CH3)3
1: Para


 


63
—H




—Cl, —OCF3
2: Meta, Para


 


64
—H




—C(CH3)3
1: Para


 


65
—H




—Cl, —OCF3
2: Meta, Para


 


66
—H




—CF3
Para


 


67
—H




—C(CH3)3
Para


 


68
—H




—Cl, —OCF3
2: Meta, Para


 


69
—H




—Br
1: Para


 


70
—H




—Br
1: Para


 


71
—H




—Br
1: Para


 


72
—H








Fused to Phenyl


 


73
—H




—CH(CH3)2
1: Para


 


74
—H




—Br
1: Para


 


75
—H








Fused to Pheyl





*Location is in reference to the attachment to the CH2 group of the benzyloxy moiety.






The following compounds of Examples 76-77 of Formula I′′′′ were prepared according to the procedure of Schemes 1-4 and Examples 1-2 and were characterized as being the indicated compound.












(I′′′′)








 










Example
R







76
—H



77
—OCH3










cFMS Assay: Filter Binding Substrate Phosphorylation Assay

The candidate inhibitor compounds of the present invention were tested for cFMS protein tyrosine kinase inhibitory activity in substrate phosphorylation assays. This assay examines the ability of small molecule organic compounds to inhibit the tyrosine phosphorylation of a peptide substrate.
The substrate phosphorylation assays use the cFMS intracellular domain, expressed in SF-9 insect cells as an amino-terminal GST tagged fusion protein. DNA encoding this recombinant protein was subcloned into the pAcGHLT-A baculovirus vector (Life Technologies, Gibco BRL). The sequence used was derived from GenBank entry X03663. The encoded sequence of the catalytic domain included amino acids 547-980.
The method measures the ability of the isolated enzyme to catalyse the transfer of the g-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide (biotin-Ahx-EEEEYFELVAKKK-amide). Substrate phosphorylation was detected by the following procedure:
cFMS kinase was “pre-activated” for 2 hours at room temperature in the presence of 100 uM ATP and 10 mM MgCl2. (It was experimentally determined that under these conditions the rate of catalysis is increased). The enzyme was subsequently diluted and incubated for 30 minutes, at room temperature, in an assay volume of 45 ul containing 10 mM MgCl2, 15 uM ATP, 5 mM DTT, 50 mM NaCl, 20 uM peptide, 0.5 mCi [g-33P] ATP/well, 50 mM MOPS, pH 7.5 and 1 ul of test compound in 100% DMSO. The reaction was stopped by the addition of an equal volume of 0.5% phosphoric acid (stop solution). 80 ul of sample was transferred to a phosphocellulose (MAPH) 96-well filter plate (Millipore Corp., Bedford, Mass.) previously pre-wet with 100 ul of stop solution. The plate was washed three times, dried and 40 ul of Optiphase SuperMix scintillation liquid (Wallac Corp., Turku, Finland) was added. The plate was sealed and counted in a Packard Topcount Microplate Scintillation Counter (Packard Instrument Co., Meriden, Conn.).
The data for dose responses were plotted as % Control calculated with the data reduction formula 100*(U1-C2)/(C1-C2) versus concentration of compound and fitted to the curve described by:

y=((Vmax*x)/(K+x))

where Vmax is the upper asymptote and K is the IC50.

The compounds of Examples 1-77 of Formula (I) showed inhibitory activity towards cFMS with a PIC50 of greater than 6.5.
Crystallization and Data Collection
Crystals were obtained with both construct 1 and 2 by the hanging drop vapor diffusion method. Construct 1 yielded crystal form I and II while construct 2 gave crystal forms III. Crystal form IV was obtained with both construct 1 and 2 in the presence of a diaminopyrimidine inhibitor. In all cases, protein (6 mg/ml in 20 mM HEPES pH 7.5, 300 mM NaCl, 5 mM DTT) was mixed with an equal volume of reservoir and incubated at 4° C. The reservoir solutions for the 4 crystal forms were:

    Crystal form I: 50-100 mM MES pH 6.5, 50-230 mM (NH4)2SO4, 8-17% PEG 5K MME.
    Crystal form II: 100-200 mM Mg2SO4, 18-24% PEG 3350
    Crystal form III: 25% PEG 3350, 0.2 M (NH4)2SO4 
    Crystal form IV: 50-100 mM MES pH 6.5, 50-230 mM (NH4)2SO4, 8-17% PEG 5K MME


Prior to data collection, glycerol and PEG 400 were added to a final concentration of 25% and 5%, respectively, and the crystals were flash frozen in liquid N2. Data for all 4 crystal forms were collected at beamline 17-ID on a MAR-CCD detector in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source, Argonne National Laboratory. These facilities are supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology (IIT), executed through the IIT's Center for Synchrotron Radiation Research and Instrumentation. The data were processed using HKL2000.
Structure Determination and Refinement
The structure of crystal form I was solved first and subsequently used to solve the other three crystal forms. The structure was solved by molecular replacement using CNS and FGFR1 as a search model (molecule 1 of PDB entry 1FGK). The search model contained FGFR1 residues 464-485, 491-500, 506-578, 592-647 and 651-761. Residues not conserved between FGFR1 and cFMS were truncated to alanine in the model. The correct solution was the top peak in both the rotation and translation functions. Rigid body refinement gave a R-factor of 49%. Multiple rounds of model building and refinement were carried out with QUANTA and CNS. The overall structure was confirmed by a composite omit map calculated with CNS. Analysis of the structure with PROCHECK indicated that all main chain torsions fall within the allowed regions of the Ramachandran plot.
The results are depicted in Tables 1 and 2.








(1) Amino acid sequence: construct 1









(SEQ ID NO: 1)









MKKGHHHHHHGQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLG



 


AGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHENIVN


 


LLGACTHGGPVLVITEYCCYGDLLNFLRRKAEAMLGPSLAPGQDPEGLDKEDGRPLELR


 


DLLHFSSQVAQGMAFLASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDIMNDSNYIVK


 


GNARLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGILVNSKFYKLVKD


 


GYQMAQPAFAPKNIYSIMQACWALEPTHRPTFQQICSFLQEQAQEDRR


 


(2) Amino acid sequence: construct 2








(SEQ ID NO: 2)









MKKGHHHHHHGQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNLQFGKTLG



 


AGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSHLGQHENIVN


 


LLGACTHGGPVLVLTEYCCYGDLLNFLRRKAEALDKEDGRPLELRDLLHFSSQVAQGMA


 


FLASKNCIHRDVAARNVLLTNGHVAKIGDFGLARDIMNDSNYIVKGNARLPVKWMAPES


 


IFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGILVNSKFYKLVKDGYQMAQPAFAPKNI


 


YSIMQACWALEPTHRPTFQQICSFLQEQAQEDRR


 


DNA sequence Construct 1 (residues 542–919Δ696–741)








(SEQ ID NO: 3)









   1 ATGAAAAAAG GTCATCATCA TCATCATCAT GGTCAGAAGC CCAAGTACCA



 


  51 GGTCCGCTGG AAGATCATCG AGAGCTATGA GGGCAACAGT TATACTTTCA


 


 101 TCGACCCCAC GCAGCTGCCT TACAACGAGA AGTGGGAGTT CCCCCGGAAC


 


 151 AACCTGCAGT TTGGTAAGAC CCTCGGAGCT GGAGCCTTTG GGAAGGTGGT


 


 201 GGAGGCCACG GCCTTTGGTC TGGGCAAGGA GGATGCTGTC CTGAAGGTGG


 


 251 CTGTGAAGAT GCTGAAGTCC ACGGCCCATG CTGATGAGAA GGAGGCCCTC


 


 301 ATGTCCGAGC TGAAGATCAT GAGCCACCTG GGCCAGCACG AGAACATCGT


 


 351 CAACCTTCTG GGAGCCTGTA CCCATGGAGG CCCTGTACTG GTCATCACGG


 


 401 AGTACTGTTG CTATGGCGAC CTGCTCAACT TTCTGCGAAG GAAGGCTGAG


 


 451 GCCATGCTGG GACCCAGCCT GGCCCCCGGC CAGGACCCCG AGGGACTGGA


 


 501 CAAGGAGGAT GGACGGCCCC TGGAGCTCCG GGACCTGCTT CACTTCTCCA


 


 551 GCCAAGTAGC CCAGGGCATG GCCTTCCTCG CTTCCAAGAA TTGCATCCAC


 


 601 CGGGACGTGG CAGCGCGTAA CGTGCTGTTG ACCAATGGTC ATGTGGCGAA


 


 651 GATTGGGGAC TTCGGGCTGG CTAGGGACAT CATGAATGAC TCCAACTACA


 


 701 TTGTCAAGGG CAATGCCCGC CTGCCTGTGA AGTGGATGGC CCCAGAGAGC


 


 751 ATCTTTGACT GTGTCTACAC GGTTCAGAGC GACGTCTGGT CCTATGGCAT


 


 801 CCTCCTCTGG GAGATCTTCT CACTTGGGCT GAATGCCTAC CCTGGCATCC


 


 851 TGGTGAACAG CAAGTTCTAT AAACTGGTGA AGGATGGATA CCAAATGGCC


 


 901 CAGCCTGCAT TTGCCCCAAA GAATATATAC AGCATCATGC AGGCCTGCTG


 


 951 GGCCTTGGAG CCCACCCACA GACCCACCTT GCAGCAGATC TGCTGCTTCC


 


1001 TTCAGGAGCA GGCCCAAGAG GACAGGAGAT AATAA


 


DNA sequence Construct 2 (residues 542–919Δ682–741)








(SEQ ID NO: 4)









  1 ATGAAAAAAG GTCATCATCA TCATCATCAT GGTCAGAAGC CCAAGTACCA



 


 51 GGTCCGCTGG AAGATCATCG AGAGCTATGA GGGCAAGAGT TATACTTTCA


 


101 TCGACCCCAC GCAGCTGCCT TACAACGAGA AGTGGGAGTT CCCCCGGAAC


 


151 AACCTGCAGT TTGGTAAGAC CCTCGGAGCT GGAGCCTTTG GGAAGGTGGT


 


201 GGAGGCCACG GCCTTTGGTC TGGGCAAGGA GGATGCTGTC CTGAAGGTGG


 


251 CTGTGAAGAT GCTGAAGTCC ACGGCCCATG CTGATGAGAA GGAGGCCCTC


 


301 ATGTCCGAGC TGAAGATCAT GAGCCACCTG GGCCAGCACG AGAACATCGT


 


351 CAACCTTCTG GGAGCCTGTA CCCATGGAGG CCCTGTACTG GTCATCACGG


 


401 AGTACTGTTG CTATGGCGAC CTGCTCAACT TTCTGCGAAG GAAGGCTGAG


 


451 GCCCTGGACA AGGAGGATGG ACGGCCCCTG GAGCTCCGGG ACCTGCTTCA


 


501 CTTCTCCAGC CAAGTAGCCC AGGGCATGGC CTTCCTCGCT TCCAAGAATT


 


551 GCATCCACCG GGACGTGGCA GCGCGTAACG TGCTGTTGAC CAATGGTCAT


 


601 GTGGCCAAGA TTGGGGACTT CGGGCTGGCT AGGGACATCA TGAATGACTC


 


651 CAACTACATT GTCAAGGGCA ATGCCCGCCT GCCTGTGAAG TGGATGGCCC


 


701 CAGAGAGGAT CTTTGACTGT GTCTACACGG TTCAGAGCGA CGTCTGGTCC


 


751 TATGGCATCC TCCTCTGGGA GATCTTCTCA CTTGGGCTGA ATCCCTACCC


 


801 TGGCATCCTG GTGAACAGCA AGTTCTATAA ACTGGTGAAG GATGGATACC


 


851 AAATGGCCCA GCCTGCATTT GCCCCAAAGA ATATATACAG CATCATGCAG


 


901 GCCTGCTGGG CCTTGGAGCC CACCCACAGA CCCACCTTCC AGCAGATCTG


 


951 CTCCTTCCTT CAGGAGCAGG CCCAAGAGGA CAGGAGATAA TAA













TABLE 1





Crystal and Data Statistics





















Crystal form
I
II
III
IV



Space Group
P43212
I222
P212121
R3



Unit cell a (Å)
62
64
65
80



Unit cell b (Å)
62
92
185
80



Unit cell c (Å)
183
134
195
78



Mol/asu
1
1
6
1



Resolution (Å)
2.7
2.9
3.0
1.8



Rsymab(%)
7.5
7.9
11
7.8



Completenessb (%)
83
99
98
98



Rcrystc (%)
20
—
20
19



Rfreed (%)
25
—
25
23







aRsym = Σhkl| □ − <□>| □Σ□, where □ is the observed intensity and <□> is the average intensity from observations of symmetry-related reflections.



bValue in parentheses is for the highest resolution shell.



cRcryst = Σhkl || Fobs | − | Fcalc ||/Σ | Fobs |, where Fobs and Fcalc are the observed and calculated structure factor amplitudes, respectively, for the hkl reflections.



dRfree is calculated for a set of reflections that were not included in atomic The application of which this description and claim(s) forms part may be used as a basis for priority in respect of any subsequent application.













TABLE 2





cFMS - Formula (Ia) compound co-crystal


resolution: 500.0-1.8 A


sg = R3 a = 80.404 b = 80.404 c = 144.968 alpha = 90 beta = 90 gamma = 120


final_r = 0.2070 free_r = 0.2467


rmsd bonds = 0.009739 rmsd angles = 1.33150


data completeness 96.6%


data collect at IMCA, −180 C, processed with HKL2000, solved with CNX

























ATOM
1
N
ALA
A
544
80.225
−70.486
87.710
1.00
37.13


ATOM
2
CA
ALA
A
544
81.411
−69.923
86.998
1.00
37.13


ATOM
3
C
ALA
A
544
81.220
−70.004
85.486
1.00
37.06


ATOM
4
O
ALA
A
544
80.845
−71.052
84.957
1.00
37.09


ATOM
5
CB
ALA
A
544
82.672
−70.685
87.407
1.00
37.16


ATOM
6
N
ALA
A
545
81.475
−68.895
84.796
1.00
36.95


ATOM
7
CA
ALA
A
545
81.342
−68.838
83.339
1.00
36.78


ATOM
8
C
ALA
A
545
82.731
−68.829
82.695
1.00
36.63


ATOM
9
O
ALA
A
545
83.720
−69.190
83.339
1.00
36.68


ATOM
10
CB
ALA
A
545
80.562
−67.588
82.936
1.00
36.81


ATOM
11
N
TYR
A
546
82.804
−68.424
81.427
1.00
36.33


ATOM
12
CA
TYR
A
546
84.085
−68.369
80.720
1.00
35.95


ATOM
13
C
TYR
A
546
84.823
−67.050
80.913
1.00
35.66


ATOM
14
O
TYR
A
546
84.218
−65.978
80.917
1.00
35.60


ATOM
15
CB
TYR
A
546
83.895
−68.607
79.216
1.00
35.90


ATOM
16
CG
TYR
A
546
85.123
−68.277
78.378
1.00
35.83


ATOM
17
CD1
TYR
A
546
85.462
−66.952
78.080
1.00
35.76


ATOM
18
CD2
TYR
A
546
85.952
−69.289
77.894
1.00
35.82


ATOM
19
CE1
TYR
A
546
86.590
−66.650
77.322
1.00
35.74


ATOM
20
CE2
TYR
A
546
87.086
−68.996
77.137
1.00
35.73


ATOM
21
CZ
TYR
A
546
87.400
−67.677
76.853
1.00
35.73


ATOM
22
OH
TYR
A
546
88.517
−67.390
76.096
1.00
35.45


ATOM
23
N
GLN
A
547
86.143
−67.153
81.042
1.00
35.34


ATOM
24
CA
GLN
A
547
87.023
−66.001
81.211
1.00
35.00


ATOM
25
C
GLN
A
547
88.308
−66.259
80.427
1.00
34.51


ATOM
26
O
GLN
A
547
88.789
−67.393
80.383
1.00
34.57


ATOM
27
CB
GLN
A
547
87.333
−65.788
82.694
1.00
35.39


ATOM
28
CG
GLN
A
547
86.234
−65.048
83.445
1.00
35.87


ATOM
29
CD
GLN
A
547
85.613
−65.873
84.559
1.00
36.21


ATOM
30
OE1
GLN
A
547
84.756
−65.385
85.305
1.00
36.47


ATOM
31
NE2
GLN
A
547
86.039
−67.129
84.679
1.00
36.36


ATOM
32
N
VAL
A
548
88.855
−65.219
79.799
1.00
33.86


ATOM
33
CA
VAL
A
548
90.070
−65.367
78.997
1.00
33.17


ATOM
34
C
VAL
A
548
91.278
−65.781
79.832
1.00
32.69


ATOM
35
O
VAL
A
548
91.859
−64.971
80.553
1.00
32.59


ATOM
36
CB
VAL
A
548
90.411
−64.068
78.240
1.00
33.12


ATOM
37
CG1
VAL
A
548
91.678
−64.266
77.429
1.00
33.07


ATOM
38
CG2
VAL
A
548
89.258
−63.682
77.316
1.00
33.11


ATOM
39
N
ARG
A
549
91.660
−67.046
79.705
1.00
32.16


ATOM
40
CA
ARG
A
549
92.779
−67.581
80.460
1.00
31.67


ATOM
41
C
ARG
A
549
94.154
−67.452
79.803
1.00
31.20


ATOM
42
O
ARG
A
549
95.162
−67.623
80.484
1.00
31.08


ATOM
43
CB
ARG
A
549
92.525
−69.051
80.820
1.00
31.84


ATOM
44
CG
ARG
A
549
91.484
−69.285
81.922
1.00
32.11


ATOM
45
CD
ARG
A
549
91.822
−70.557
82.710
1.00
32.33


ATOM
46
NE
ARG
A
549
92.105
−70.271
84.118
1.00
32.88


ATOM
47
CZ
ARG
A
549
92.863
−71.028
84.907
1.00
33.02


ATOM
48
NH1
ARG
A
549
93.432
−72.130
84.436
1.00
33.01


ATOM
49
NH2
ARG
A
549
93.053
−70.683
86.179
1.00
33.34


ATOM
50
N
TRP
A
550
94.220
−67.170
78.501
1.00
30.66


ATOM
51
CA
TRP
A
550
95.536
−67.026
77.873
1.00
30.31


ATOM
52
C
TRP
A
550
96.177
−65.812
78.528
1.00
30.33


ATOM
53
O
TRP
A
550
95.487
−64.849
78.861
1.00
30.12


ATOM
54
CB
TRP
A
550
95.448
−66.773
76.362
1.00
29.95


ATOM
55
CG
TRP
A
550
94.395
−67.550
75.638
1.00
29.51


ATOM
56
CD1
TRP
A
550
94.036
−68.851
75.849
1.00
29.35


ATOM
57
CD2
TRP
A
550
93.553
−67.064
74.589
1.00
29.27


ATOM
58
NE1
TRP
A
550
93.015
−69.201
75.001
1.00
29.14


ATOM
59
CE2
TRP
A
550
92.699
−68.124
74.215
1.00
29.21


ATOM
60
CE3
TRP
A
550
93.436
−65.835
73.928
1.00
29.22


ATOM
61
CZ2
TRP
A
550
91.736
−67.992
73.207
1.00
29.14


ATOM
62
CZ3
TRP
A
550
92.477
−65.703
72.922
1.00
29.20


ATOM
63
CH2
TRP
A
550
91.641
−66.779
72.575
1.00
29.07


ATOM
64
N
LYS
A
551
97.492
−65.839
78.710
1.00
30.43


ATOM
65
CA
LYS
A
551
98.135
−64.701
79.345
1.00
30.58


ATOM
66
C
LYS
A
551
99.603
−64.500
79.006
1.00
30.62


ATOM
67
O
LYS
A
551
100.368
−65.462
78.883
1.00
30.49


ATOM
68
CB
LYS
A
551
97.987
−64.808
80.862
1.00
30.78


ATOM
69
CG
LYS
A
551
98.454
−63.572
81.602
1.00
31.23


ATOM
70
CD
LYS
A
551
98.270
−63.721
83.104
1.00
31.47


ATOM
71
CE
LYS
A
551
98.737
−62.469
83.832
1.00
31.63


ATOM
72
NZ
LYS
A
551
98.647
−62.635
85.313
1.00
31.99


ATOM
73
N
ILE
A
552
99.974
−63.231
78.860
1.00
30.58


ATOM
74
CA
ILE
A
552
101.345
−62.835
78.578
1.00
30.55


ATOM
75
C
ILE
A
552
101.935
−62.509
79.942
1.00
30.69


ATOM
76
O
ILE
A
552
101.557
−61.517
80.564
1.00
30.57


ATOM
77
CB
ILE
A
552
101.401
−61.574
77.703
1.00
30.52


ATOM
78
CG1
ILE
A
552
100.639
−61.811
76.394
1.00
30.50


ATOM
79
CG2
ILE
A
552
102.846
−61.192
77.440
1.00
30.43


ATOM
80
CD1
ILE
A
552
101.105
−63.022
75.609
1.00
30.42


ATOM
81
N
ILE
A
553
102.854
−63.348
80.405
1.00
30.67


ATOM
82
CA
ILE
A
553
103.463
−63.157
81.711
1.00
30.75


ATOM
83
C
ILE
A
553
104.845
−62.537
81.622
1.00
30.99


ATOM
84
O
ILE
A
553
105.433
−62.438
80.549
1.00
30.74


ATOM
85
CB
ILE
A
553
103.593
−64.496
82.471
1.00
30.72


ATOM
86
CG1
ILE
A
553
104.443
−65.471
81.656
1.00
30.65


ATOM
87
CG2
ILE
A
553
102.215
−65.080
82.753
1.00
30.73


ATOM
88
CD1
ILE
A
553
104.636
−66.816
82.334
1.00
30.60


ATOM
89
N
GLU
A
554
105.363
−62.127
82.772
1.00
31.35


ATOM
90
CA
GLU
A
554
106.680
−61.524
82.819
1.00
31.79


ATOM
91
C
GLU
A
554
107.735
−62.607
83.009
1.00
31.87


ATOM
92
O
GLU
A
554
107.477
−63.644
83.626
1.00
31.77


ATOM
93
CB
GLU
A
554
106.730
−60.489
83.942
1.00
32.19


ATOM
94
CG
GLU
A
554
105.620
−59.454
83.807
1.00
32.84


ATOM
95
CD
GLU
A
554
105.917
−58.154
84.530
1.00
33.28


ATOM
96
OE1
GLU
A
554
105.982
−58.156
85.784
1.00
33.48


ATOM
97
OE2
GLU
A
554
106.085
−57.129
83.831
1.00
33.55


ATOM
98
N
SER
A
555
108.915
−62.365
82.447
1.00
32.04


ATOM
99
CA
SER
A
555
110.029
−63.305
82.519
1.00
32.22


ATOM
100
C
SER
A
555
111.338
−62.538
82.606
1.00
32.38


ATOM
101
O
SER
A
555
111.660
−61.751
81.721
1.00
32.25


ATOM
102
CB
SER
A
555
110.059
−64.191
81.274
1.00
32.22


ATOM
103
OG
SER
A
555
111.172
−65.067
81.307
1.00
32.41


ATOM
104
N
TYR
A
556
112.090
−62.778
83.673
1.00
32.61


ATOM
105
CA
TYR
A
556
113.362
−62.102
83.866
1.00
32.85


ATOM
106
C
TYR
A
556
114.510
−63.072
83.655
1.00
33.03


ATOM
107
O
TYR
A
556
114.453
−64.222
84.081
1.00
33.12


ATOM
108
CB
TYR
A
556
113.416
−61.488
85.264
1.00
32.87


ATOM
109
CG
TYR
A
556
112.339
−60.451
85.488
1.00
32.94


ATOM
110
CD1
TYR
A
556
111.442
−60.567
86.544
1.00
33.02


ATOM
111
CD2
TYR
A
556
112.220
−59.349
84.642
1.00
33.01


ATOM
112
CE1
TYR
A
556
110.447
−59.610
86.755
1.00
33.16


ATOM
113
CE2
TYR
A
556
111.237
−58.388
84.842
1.00
33.10


ATOM
114
CZ
TYR
A
556
110.352
−58.524
85.899
1.00
33.13


ATOM
115
OH
TYR
A
556
109.361
−57.588
86.088
1.00
33.31


ATOM
116
N
GLU
A
557
115.545
−62.595
82.976
1.00
33.23


ATOM
117
CA
GLU
A
557
116.715
−63.407
82.670
1.00
33.37


ATOM
118
C
GLU
A
557
116.309
−64.680
81.926
1.00
33.26


ATOM
119
O
GLU
A
557
116.983
−65.709
82.014
1.00
33.30


ATOM
120
CB
GLU
A
557
117.469
−63.761
83.952
1.00
33.63


ATOM
121
CG
GLU
A
557
117.861
−62.554
84.787
1.00
33.96


ATOM
122
CD
GLU
A
557
118.939
−62.881
85.806
1.00
34.20


ATOM
123
OE1
GLU
A
557
120.138
−62.794
85.450
1.00
34.41


ATOM
124
OE2
GLU
A
557
118.587
−63.234
86.954
1.00
34.24


ATOM
125
N
GLY
A
558
115.194
−64.599
81.205
1.00
33.09


ATOM
126
CA
GLY
A
558
114.717
−65.733
80.432
1.00
32.70


ATOM
127
C
GLY
A
558
115.098
−65.478
78.986
1.00
32.41


ATOM
128
O
GLY
A
558
115.759
−64.477
78.700
1.00
32.48


ATOM
129
N
ASN
A
559
114.701
−66.363
78.075
1.00
32.06


ATOM
130
CA
ASN
A
559
115.029
−66.169
76.667
1.00
31.62


ATOM
131
C
ASN
A
559
114.264
−64.993
76.072
1.00
31.15


ATOM
132
O
ASN
A
559
114.774
−64.288
75.205
1.00
31.16


ATOM
133
CB
ASN
A
559
114.717
−67.425
75.853
1.00
31.88


ATOM
134
CG
ASN
A
559
115.551
−68.615
76.273
1.00
32.17


ATOM
135
OD1
ASN
A
559
116.687
−68.466
76.736
1.00
32.31


ATOM
136
ND2
ASN
A
559
114.996
−69.810
76.101
1.00
32.29


ATOM
137
N
SER
A
560
113.037
−64.784
76.537
1.00
30.57


ATOM
138
CA
SER
A
560
112.216
−63.696
76.018
1.00
29.96


ATOM
139
C
SER
A
560
111.812
−62.688
77.076
1.00
29.43


ATOM
140
O
SER
A
560
111.746
−63.000
78.260
1.00
29.43


ATOM
141
CB
SER
A
560
110.973
−64.257
75.332
1.00
29.98


ATOM
142
OG
SER
A
560
111.322
−64.825
74.087
1.00
30.16


ATOM
143
N
TYR
A
561
111.522
−61.474
76.628
1.00
28.87


ATOM
144
CA
TYR
A
561
111.162
−60.395
77.534
1.00
28.19


ATOM
145
C
TYR
A
561
109.805
−59.825
77.179
1.00
27.87


ATOM
146
O
TYR
A
561
109.488
−59.627
76.009
1.00
27.73


ATOM
147
CB
TYR
A
561
112.229
−59.298
77.457
1.00
27.98


ATOM
148
CG
TYR
A
561
112.173
−58.279
78.570
1.00
27.66


ATOM
149
CD1
TYR
A
561
111.344
−57.162
78.489
1.00
27.52


ATOM
150
CD2
TYR
A
561
112.951
−58.441
79.714
1.00
27.57


ATOM
151
CE1
TYR
A
561
111.294
−56.230
79.529
1.00
27.45


ATOM
152
CE2
TYR
A
561
112.909
−57.524
80.753
1.00
27.46


ATOM
153
CZ
TYR
A
561
112.081
−56.422
80.659
1.00
27.40


ATOM
154
OH
TYR
A
561
112.040
−55.529
81.703
1.00
27.25


ATOM
155
N
THR
A
562
109.008
−59.570
78.204
1.00
27.55


ATOM
156
CA
THR
A
562
107.679
−59.018
78.031
1.00
27.43


ATOM
157
C
THR
A
562
107.721
−57.506
78.253
1.00
27.52


ATOM
158
O
THR
A
562
107.795
−57.045
79.391
1.00
27.46


ATOM
159
CB
THR
A
562
106.708
−59.659
79.032
1.00
27.33


ATOM
160
OG1
THR
A
562
106.634
−61.066
78.770
1.00
27.20


ATOM
161
CG2
THR
A
562
105.320
−59.035
78.928
1.00
27.27


ATOM
162
N
PHE
A
563
107.682
−56.750
77.159
1.00
27.54


ATOM
163
CA
PHE
A
563
107.710
−55.292
77.218
1.00
27.78


ATOM
164
C
PHE
A
563
106.324
−54.712
77.454
1.00
28.04


ATOM
165
O
PHE
A
563
106.183
−53.670
78.088
1.00
27.87


ATOM
166
CB
PHE
A
563
108.278
−54.716
75.917
1.00
27.67


ATOM
167
CG
PHE
A
563
109.762
−54.874
75.780
1.00
27.56


ATOM
168
CD1
PHE
A
563
110.630
−54.027
76.465
1.00
27.48


ATOM
169
CD2
PHE
A
563
110.295
−55.876
74.980
1.00
27.57


ATOM
170
CE1
PHE
A
563
112.007
−54.174
76.356
1.00
27.42


ATOM
171
CE2
PHE
A
563
111.677
−56.034
74.863
1.00
27.61


ATOM
172
CZ
PHE
A
563
112.534
−55.177
75.555
1.00
27.55


ATOM
173
N
ILE
A
564
105.300
−55.391
76.947
1.00
28.42


ATOM
174
CA
ILE
A
564
103.934
−54.908
77.102
1.00
28.96


ATOM
175
C
ILE
A
564
102.904
−55.997
77.376
1.00
29.47


ATOM
176
O
ILE
A
564
103.147
−57.183
77.142
1.00
29.41


ATOM
177
CB
ILE
A
564
103.477
−54.168
75.838
1.00
28.90


ATOM
178
CG1
ILE
A
564
103.546
−55.122
74.636
1.00
28.90


ATOM
179
CG2
ILE
A
564
104.335
−52.937
75.620
1.00
28.93


ATOM
180
CD1
ILE
A
564
103.064
−54.532
73.332
1.00
28.90


ATOM
181
N
ASP
A
565
101.747
−55.572
77.871
1.00
30.06


ATOM
182
CA
ASP
A
565
100.633
−56.475
78.144
1.00
30.72


ATOM
183
C
ASP
A
565
99.517
−55.991
77.226
1.00
31.12


ATOM
184
O
ASP
A
565
98.835
−55.010
77.519
1.00
31.11


ATOM
185
CB
ASP
A
565
100.201
−56.389
79.606
1.00
30.96


ATOM
186
CG
ASP
A
565
98.998
−57.264
79.908
1.00
31.26


ATOM
187
OD1
ASP
A
565
98.928
−58.398
79.384
1.00
31.37


ATOM
188
OD2
ASP
A
565
98.123
−56.821
80.677
1.00
31.57


ATOM
189
N
PRO
A
566
99.323
−56.681
76.095
1.00
31.48


ATOM
190
CA
PRO
A
566
98.308
−56.351
75.093
1.00
31.84


ATOM
191
C
PRO
A
566
96.875
−56.173
75.593
1.00
32.24


ATOM
192
O
PRO
A
566
96.094
−55.449
74.974
1.00
32.33


ATOM
193
CB
PRO
A
566
98.442
−57.492
74.085
1.00
31.75


ATOM
194
CG
PRO
A
566
98.866
−58.646
74.949
1.00
31.63


ATOM
195
CD
PRO
A
566
99.907
−58.009
75.827
1.00
31.54


ATOM
196
N
THR
A
567
96.532
−56.813
76.708
1.00
32.70


ATOM
197
CA
THR
A
567
95.179
−56.721
77.244
1.00
33.22


ATOM
198
C
THR
A
567
94.922
−55.428
78.003
1.00
33.59


ATOM
199
O
THR
A
567
93.784
−55.140
78.381
1.00
33.64


ATOM
200
CB
THR
A
567
94.864
−57.891
78.183
1.00
33.27


ATOM
201
OG1
THR
A
567
95.633
−57.760
79.384
1.00
33.40


ATOM
202
CG2
THR
A
567
95.199
−59.220
77.506
1.00
33.33


ATOM
203
N
GLN
A
568
95.977
−54.653
78.236
1.00
33.98


ATOM
204
CA
GLN
A
568
95.837
−53.384
78.941
1.00
34.34


ATOM
205
C
GLN
A
568
96.027
−52.252
77.952
1.00
34.50


ATOM
206
O
GLN
A
568
95.979
−51.076
78.313
1.00
34.53


ATOM
207
CB
GLN
A
568
96.870
−53.266
80.063
1.00
34.56


ATOM
208
CG
GLN
A
568
96.678
−54.273
81.176
1.00
35.03


ATOM
209
CD
GLN
A
568
95.218
−54.430
81.555
1.00
35.26


ATOM
210
OE1
GLN
A
568
94.534
−53.447
81.854
1.00
35.51


ATOM
211
NE2
GLN
A
568
94.729
−55.670
81.538
1.00
35.42


ATOM
212
N
LEU
A
569
96.246
−52.621
76.698
1.00
34.60


ATOM
213
CA
LEU
A
569
96.454
−51.645
75.640
1.00
34.73


ATOM
214
C
LEU
A
569
95.278
−51.660
74.672
1.00
34.85


ATOM
215
O
LEU
A
569
94.518
−52.630
74.615
1.00
34.79


ATOM
216
CB
LEU
A
569
97.759
−51.954
74.904
1.00
34.76


ATOM
217
CG
LEU
A
569
98.986
−51.939
75.824
1.00
34.76


ATOM
218
CD1
LEU
A
569
100.215
−52.421
75.074
1.00
34.77


ATOM
219
CD2
LEU
A
569
99.196
−50.528
76.355
1.00
34.81


ATOM
220
N
PRO
A
570
95.106
−50.577
73.901
1.00
34.90


ATOM
221
CA
PRO
A
570
93.994
−50.527
72.952
1.00
34.94


ATOM
222
C
PRO
A
570
94.153
−51.470
71.764
1.00
35.02


ATOM
223
O
PRO
A
570
95.260
−51.901
71.428
1.00
34.92


ATOM
224
CB
PRO
A
570
93.973
−49.059
72.527
1.00
34.99


ATOM
225
CG
PRO
A
570
95.424
−48.680
72.587
1.00
34.91


ATOM
226
CD
PRO
A
570
95.867
−49.313
73.889
1.00
34.90


ATOM
227
N
TYR
A
571
93.027
−51.795
71.143
1.00
35.04


ATOM
228
CA
TYR
A
571
93.012
−52.653
69.972
1.00
35.17


ATOM
229
C
TYR
A
571
93.806
−51.948
68.875
1.00
35.30


ATOM
230
O
TYR
A
571
93.682
−50.735
68.687
1.00
35.24


ATOM
231
CB
TYR
A
571
91.564
−52.873
69.528
1.00
35.16


ATOM
232
CG
TYR
A
571
91.384
−53.238
68.072
1.00
35.19


ATOM
233
CD1
TYR
A
571
91.749
−54.495
67.592
1.00
35.20


ATOM
234
CD2
TYR
A
571
90.822
−52.327
67.176
1.00
35.23


ATOM
235
CE1
TYR
A
571
91.554
−54.836
66.257
1.00
35.26


ATOM
236
CE2
TYR
A
571
90.624
−52.657
65.844
1.00
35.24


ATOM
237
CZ
TYR
A
571
90.987
−53.910
65.389
1.00
35.32


ATOM
238
OH
TYR
A
571
90.761
−54.240
64.072
1.00
35.35


ATOM
239
N
ASN
A
572
94.635
−52.705
68.166
1.00
35.50


ATOM
240
CA
ASN
A
572
95.440
−52.151
67.085
1.00
35.78


ATOM
241
C
ASN
A
572
94.583
−52.024
65.827
1.00
36.01


ATOM
242
O
ASN
A
572
94.344
−53.015
65.134
1.00
36.05


ATOM
243
CB
ASN
A
572
96.636
−53.060
66.804
1.00
35.74


ATOM
244
CG
ASN
A
572
97.491
−52.556
65.664
1.00
35.82


ATOM
245
OD1
ASN
A
572
97.199
−51.518
65.068
1.00
35.83


ATOM
246
ND2
ASN
A
572
98.557
−53.286
65.352
1.00
35.84


ATOM
247
N
GLU
A
573
94.135
−50.803
65.538
1.00
36.26


ATOM
248
CA
GLU
A
573
93.287
−50.525
64.378
1.00
36.59


ATOM
249
C
GLU
A
573
93.759
−51.102
63.045
1.00
36.83


ATOM
250
O
GLU
A
573
92.948
−51.331
62.153
1.00
36.83


ATOM
251
CB
GLU
A
573
93.082
−49.014
64.220
1.00
36.55


ATOM
252
CG
GLU
A
573
92.232
−48.354
65.301
1.00
36.64


ATOM
253
CD
GLU
A
573
90.776
−48.803
65.277
1.00
36.68


ATOM
254
OE1
GLU
A
573
90.206
−48.931
64.168
1.00
36.71


ATOM
255
OE2
GLU
A
573
90.198
−49.011
66.367
1.00
36.65


ATOM
256
N
LYS
A
574
95.057
−51.342
62.897
1.00
37.21


ATOM
257
CA
LYS
A
574
95.563
−51.893
61.640
1.00
37.65


ATOM
258
C
LYS
A
574
95.011
−53.275
61.283
1.00
37.86


ATOM
259
O
LYS
A
574
95.363
−53.841
60.247
1.00
37.85


ATOM
260
CB
LYS
A
574
97.092
−51.946
61.646
1.00
37.76


ATOM
261
CG
LYS
A
574
97.749
−50.586
61.451
1.00
37.89


ATOM
262
CD
LYS
A
574
99.184
−50.725
60.965
1.00
38.01


ATOM
263
CE
LYS
A
574
99.789
−49.365
60.635
1.00
38.11


ATOM
264
NZ
LYS
A
574
101.209
−49.482
60.195
1.00
38.17


ATOM
265
N
TRP
A
575
94.153
−53.820
62.139
1.00
38.15


ATOM
266
CA
TRP
A
575
93.561
−55.128
61.879
1.00
38.46


ATOM
267
C
TRP
A
575
92.136
−54.977
61.354
1.00
38.76


ATOM
268
O
TRP
A
575
91.531
−55.946
60.890
1.00
38.70


ATOM
269
CB
TRP
A
575
93.522
−55.978
63.154
1.00
38.33


ATOM
270
CG
TRP
A
575
94.849
−56.468
63.647
1.00
38.19


ATOM
271
CD1
TRP
A
575
95.604
−55.928
64.651
1.00
38.15


ATOM
272
CD2
TRP
A
575
95.563
−57.622
63.185
1.00
38.13


ATOM
273
NE1
TRP
A
575
96.742
−56.678
64.845
1.00
38.09


ATOM
274
CE2
TRP
A
575
96.742
−57.723
63.959
1.00
38.08


ATOM
275
CE3
TRP
A
575
95.319
−58.584
62.194
1.00
38.12


ATOM
276
CZ2
TRP
A
575
97.676
−58.747
63.773
1.00
38.01


ATOM
277
CZ3
TRP
A
575
96.251
−59.606
62.008
1.00
38.02


ATOM
278
CH2
TRP
A
575
97.415
−59.677
62.797
1.00
38.06


ATOM
279
N
GLU
A
576
91.610
−53.759
61.429
1.00
39.16


ATOM
280
CA
GLU
A
576
90.244
−53.469
61.001
1.00
39.66


ATOM
281
C
GLU
A
576
89.957
−53.880
59.551
1.00
39.93


ATOM
282
O
GLU
A
576
90.786
−53.696
58.657
1.00
39.91


ATOM
283
CB
GLU
A
576
89.955
−51.980
61.202
1.00
39.69


ATOM
284
CG
GLU
A
576
88.481
−51.610
61.252
1.00
39.89


ATOM
285
CD
GLU
A
576
87.746
−52.224
62.434
1.00
40.01


ATOM
286
OE1
GLU
A
576
88.327
−52.311
63.541
1.00
40.02


ATOM
287
OE2
GLU
A
576
86.570
−52.604
62.259
1.00
40.10


ATOM
288
N
PHE
A
577
88.770
−54.450
59.343
1.00
40.30


ATOM
289
CA
PHE
A
577
88.323
−54.926
58.033
1.00
40.66


ATOM
290
C
PHE
A
577
86.880
−54.457
57.829
1.00
40.93


ATOM
291
O
PHE
A
577
86.107
−54.387
58.784
1.00
40.94


ATOM
292
CB
PHE
A
577
88.387
−56.457
58.001
1.00
40.64


ATOM
293
CG
PHE
A
577
88.070
−57.061
56.660
1.00
40.67


ATOM
294
CD1
PHE
A
577
88.947
−56.918
55.591
1.00
40.61


ATOM
295
CD2
PHE
A
577
86.896
−57.786
56.470
1.00
40.67


ATOM
296
CE1
PHE
A
577
88.660
−57.489
54.352
1.00
40.64


ATOM
297
CE2
PHE
A
577
86.601
−58.362
55.232
1.00
40.68


ATOM
298
CZ
PHE
A
577
87.486
−58.213
54.172
1.00
40.61


ATOM
299
N
PRO
A
578
86.499
−54.126
56.581
1.00
41.28


ATOM
300
CA
PRO
A
578
85.134
−53.664
56.299
1.00
41.53


ATOM
301
C
PRO
A
578
84.060
−54.709
56.599
1.00
41.72


ATOM
302
O
PRO
A
578
84.064
−55.795
56.030
1.00
41.78


ATOM
303
CB
PRO
A
578
85.191
−53.305
54.814
1.00
41.51


ATOM
304
CG
PRO
A
578
86.630
−52.923
54.607
1.00
41.47


ATOM
305
CD
PRO
A
578
87.342
−54.010
55.378
1.00
41.37


ATOM
306
N
ARG
A
579
83.144
−54.361
57.496
1.00
41.99


ATOM
307
CA
ARG
A
579
82.051
−55.237
57.897
1.00
42.27


ATOM
308
C
ARG
A
579
81.241
−55.696
56.690
1.00
42.50


ATOM
309
O
ARG
A
579
80.960
−56.885
56.531
1.00
42.58


ATOM
310
CB
ARG
A
579
81.145
−54.490
58.875
1.00
42.34


ATOM
311
CG
ARG
A
579
79.929
−55.253
59.348
1.00
42.36


ATOM
312
CD
ARG
A
579
79.144
−54.381
60.301
1.00
42.48


ATOM
313
NE
ARG
A
579
79.999
−53.895
61.380
1.00
42.58


ATOM
314
CZ
ARG
A
579
80.487
−54.661
62.352
1.00
42.56


ATOM
315
NH1
ARG
A
579
80.202
−55.956
62.390
1.00
42.52


ATOM
316
NH2
ARG
A
579
81.272
−54.132
63.281
1.00
42.58


ATOM
317
N
ASN
A
580
80.870
−54.738
55.844
1.00
42.69


ATOM
318
CA
ASN
A
580
80.090
−55.008
54.636
1.00
42.82


ATOM
319
C
ASN
A
580
80.803
−55.935
53.659
1.00
42.76


ATOM
320
O
ASN
A
580
80.180
−56.473
52.746
1.00
42.87


ATOM
321
CB
ASN
A
580
79.764
−53.699
53.918
1.00
43.01


ATOM
322
CG
ASN
A
580
78.825
−52.816
54.711
1.00
43.27


ATOM
323
OD1
ASN
A
580
77.654
−53.154
54.909
1.00
43.47


ATOM
324
ND2
ASN
A
580
79.333
−51.677
55.173
1.00
43.40


ATOM
325
N
ASN
A
581
82.106
−56.122
53.842
1.00
42.68


ATOM
326
CA
ASN
A
581
82.859
−56.985
52.941
1.00
42.55


ATOM
327
C
ASN
A
581
83.101
−58.388
53.488
1.00
42.43


ATOM
328
O
ASN
A
581
84.174
−58.953
53.319
1.00
42.39


ATOM
329
CB
ASN
A
581
84.193
−56.332
52.575
1.00
42.62


ATOM
330
CG
ASN
A
581
84.011
−54.973
51.921
1.00
42.71


ATOM
331
OD1
ASN
A
581
82.922
−54.641
51.447
1.00
42.69


ATOM
332
ND2
ASN
A
581
85.081
−54.186
51.879
1.00
42.75


ATOM
333
N
LEU
A
582
82.098
−58.938
54.163
1.00
42.31


ATOM
334
CA
LEU
A
582
82.190
−60.291
54.699
1.00
42.14


ATOM
335
C
LEU
A
582
80.919
−61.039
54.341
1.00
41.96


ATOM
336
O
LEU
A
582
79.820
−60.600
54.678
1.00
42.01


ATOM
337
CB
LEU
A
582
82.357
−60.279
56.222
1.00
42.15


ATOM
338
CG
LEU
A
582
83.762
−60.160
56.817
1.00
42.12


ATOM
339
CD1
LEU
A
582
83.670
−60.331
58.333
1.00
42.12


ATOM
340
CD2
LEU
A
582
84.677
−61.218
56.229
1.00
42.11


ATOM
341
N
GLN
A
583
81.066
−62.163
53.650
1.00
41.77


ATOM
342
CA
GLN
A
583
79.909
−62.962
53.270
1.00
41.51


ATOM
343
C
GLN
A
583
79.894
−64.255
54.067
1.00
41.09


ATOM
344
O
GLN
A
583
80.542
−65.234
53.706
1.00
41.12


ATOM
345
CB
GLN
A
583
79.934
−63.239
51.768
1.00
41.83


ATOM
346
CG
GLN
A
583
79.855
−61.951
50.951
1.00
42.29


ATOM
347
CD
GLN
A
583
79.600
−62.187
49.476
1.00
42.55


ATOM
348
OE1
GLN
A
583
79.547
−61.238
48.690
1.00
42.66


ATOM
349
NE2
GLN
A
583
79.437
−63.453
49.090
1.00
42.69


ATOM
350
N
PHE
A
584
79.149
−64.233
55.165
1.00
40.62


ATOM
351
CA
PHE
A
584
79.047
−65.375
56.059
1.00
40.03


ATOM
352
C
PHE
A
584
78.452
−66.603
55.397
1.00
39.47


ATOM
353
O
PHE
A
584
77.542
−66.506
54.571
1.00
39.50


ATOM
354
CB
PHE
A
584
78.222
−65.003
57.297
1.00
40.28


ATOM
355
CG
PHE
A
584
78.763
−63.818
58.053
1.00
40.48


ATOM
356
CD1
PHE
A
584
80.110
−63.747
58.391
1.00
40.54


ATOM
357
CD2
PHE
A
584
77.927
−62.768
58.418
1.00
40.59


ATOM
358
CE1
PHE
A
584
80.618
−62.647
59.078
1.00
40.58


ATOM
359
CE2
PHE
A
584
78.427
−61.663
59.106
1.00
40.67


ATOM
360
CZ
PHE
A
584
79.775
−61.604
59.435
1.00
40.62


ATOM
361
N
GLY
A
585
78.986
−67.761
55.771
1.00
38.75


ATOM
362
CA
GLY
A
585
78.513
−69.020
55.232
1.00
37.75


ATOM
363
C
GLY
A
585
77.914
−69.888
56.319
1.00
37.02


ATOM
364
O
GLY
A
585
77.185
−69.400
57.182
1.00
37.08


ATOM
365
N
LYS
A
586
78.236
−71.176
56.286
1.00
36.26


ATOM
366
CA
LYS
A
586
77.713
−72.132
57.257
1.00
35.43


ATOM
367
C
LYS
A
586
78.343
−71.978
58.637
1.00
34.71


ATOM
368
O
LYS
A
586
79.456
−71.473
58.775
1.00
34.59


ATOM
369
CB
LYS
A
586
77.955
−73.563
56.761
1.00
35.62


ATOM
370
CG
LYS
A
586
79.429
−73.960
56.748
1.00
35.80


ATOM
371
CD
LYS
A
586
79.662
−75.363
56.203
1.00
36.01


ATOM
372
CE
LYS
A
586
81.151
−75.692
56.215
1.00
36.22


ATOM
373
NZ
LYS
A
586
81.483
−76.976
55.527
1.00
36.39


ATOM
374
N
THR
A
587
77.617
−72.421
59.655
1.00
33.87


ATOM
375
CA
THR
A
587
78.107
−72.375
61.026
1.00
33.03


ATOM
376
C
THR
A
587
79.148
−73.482
61.177
1.00
32.41


ATOM
377
O
THR
A
587
78.978
−74.579
60.639
1.00
32.36


ATOM
378
CB
THR
A
587
76.971
−72.626
62.031
1.00
33.09


ATOM
379
OG1
THR
A
587
76.047
−71.529
61.990
1.00
33.17


ATOM
380
CG2
THR
A
587
77.528
−72.775
63.443
1.00
33.00


ATOM
381
N
LEU
A
588
80.229
−73.191
61.893
1.00
31.58


ATOM
382
CA
LEU
A
588
81.285
−74.175
62.105
1.00
30.83


ATOM
383
C
LEU
A
588
81.256
−74.695
63.533
1.00
30.32


ATOM
384
O
LEU
A
588
81.690
−75.807
63.805
1.00
30.19


ATOM
385
CB
LEU
A
588
82.658
−73.558
61.811
1.00
30.72


ATOM
386
CG
LEU
A
588
82.930
−73.119
60.368
1.00
30.61


ATOM
387
CD1
LEU
A
588
84.293
−72.455
60.291
1.00
30.54


ATOM
388
CD2
LEU
A
588
82.866
−74.321
59.431
1.00
30.61


ATOM
389
N
GLY
A
589
80.741
−73.881
64.445
1.00
29.92


ATOM
390
CA
GLY
A
589
80.671
−74.291
65.834
1.00
29.41


ATOM
391
C
GLY
A
589
80.174
−73.178
66.726
1.00
29.06


ATOM
392
O
GLY
A
589
80.103
−72.028
66.307
1.00
28.99


ATOM
393
N
ALA
A
590
79.833
−73.516
67.963
1.00
28.79


ATOM
394
CA
ALA
A
590
79.340
−72.523
68.906
1.00
28.53


ATOM
395
C
ALA
A
590
79.576
−73.007
70.326
1.00
28.37


ATOM
396
O
ALA
A
590
79.812
−74.193
70.549
1.00
28.17


ATOM
397
CB
ALA
A
590
77.851
−72.263
68.670
1.00
28.38


ATOM
398
N
GLY
A
591
79.519
−72.083
71.280
1.00
28.34


ATOM
399
CA
GLY
A
591
79.743
−72.441
72.668
1.00
28.47


ATOM
400
C
GLY
A
591
79.073
−71.538
73.692
1.00
28.59


ATOM
401
O
GLY
A
591
78.004
−70.971
73.444
1.00
28.58


ATOM
402
N
ALA
A
592
79.717
−71.403
74.849
1.00
28.63


ATOM
403
CA
ALA
A
592
79.198
−70.598
75.954
1.00
28.71


ATOM
404
C
ALA
A
592
78.799
−69.173
75.596
1.00
28.79


ATOM
405
O
ALA
A
592
77.666
−68.767
75.854
1.00
28.71


ATOM
406
CB
ALA
A
592
80.208
−70.575
77.096
1.00
28.67


ATOM
407
N
PHE
A
593
79.722
−68.417
75.007
1.00
28.96


ATOM
408
CA
PHE
A
593
79.452
−67.022
74.652
1.00
29.22


ATOM
409
C
PHE
A
593
79.387
−66.680
73.174
1.00
29.29


ATOM
410
O
PHE
A
593
78.704
−65.731
72.791
1.00
29.31


ATOM
411
CB
PHE
A
593
80.494
−66.097
75.282
1.00
29.43


ATOM
412
CG
PHE
A
593
80.440
−66.044
76.774
1.00
29.75


ATOM
413
CD1
PHE
A
593
79.358
−66.576
77.469
1.00
29.79


ATOM
414
CD2
PHE
A
593
81.473
−65.450
77.490
1.00
29.88


ATOM
415
CE1
PHE
A
593
79.304
−66.520
78.855
1.00
30.00


ATOM
416
CE2
PHE
A
593
81.430
−65.387
78.881
1.00
29.97


ATOM
417
CZ
PHE
A
593
80.343
−65.924
79.563
1.00
30.03


ATOM
418
N
GLY
A
594
80.102
−67.430
72.344
1.00
29.41


ATOM
419
CA
GLY
A
594
80.103
−67.113
70.930
1.00
29.52


ATOM
420
C
GLY
A
594
79.863
−68.241
69.953
1.00
29.74


ATOM
421
O
GLY
A
594
79.682
−69.402
70.328
1.00
29.64


ATOM
422
N
LYS
A
595
79.877
−67.876
68.678
1.00
29.95


ATOM
423
CA
LYS
A
595
79.664
−68.814
67.587
1.00
30.31


ATOM
424
C
LYS
A
595
80.718
−68.521
66.521
1.00
30.44


ATOM
425
O
LYS
A
595
81.239
−67.403
66.439
1.00
30.34


ATOM
426
CB
LYS
A
595
78.258
−68.620
67.011
1.00
30.51


ATOM
427
CG
LYS
A
595
78.026
−67.201
66.506
1.00
30.82


ATOM
428
CD
LYS
A
595
76.582
−66.734
66.674
1.00
31.02


ATOM
429
CE
LYS
A
595
75.640
−67.346
65.663
1.00
31.21


ATOM
430
NZ
LYS
A
595
74.275
−66.732
65.777
1.00
31.33


ATOM
431
N
VAL
A
596
81.042
−69.529
65.720
1.00
30.59


ATOM
432
CA
VAL
A
596
82.022
−69.373
64.657
1.00
30.88


ATOM
433
C
VAL
A
596
81.364
−69.750
63.337
1.00
31.30


ATOM
434
O
VAL
A
596
80.774
−70.829
63.206
1.00
31.13


ATOM
435
CB
VAL
A
596
83.257
−70.274
64.888
1.00
30.78


ATOM
436
CG1
VAL
A
596
84.292
−70.032
63.798
1.00
30.74


ATOM
437
CG2
VAL
A
596
83.858
−69.991
66.251
1.00
30.68


ATOM
438
N
VAL
A
597
81.461
−68.856
62.362
1.00
31.82


ATOM
439
CA
VAL
A
597
80.863
−69.098
61.059
1.00
32.51


ATOM
440
C
VAL
A
597
81.899
−69.018
59.946
1.00
33.15


ATOM
441
O
VAL
A
597
82.909
−68.324
60.060
1.00
33.04


ATOM
442
CB
VAL
A
597
79.744
−68.071
60.753
1.00
32.44


ATOM
443
CG1
VAL
A
597
78.744
−68.028
61.895
1.00
32.25


ATOM
444
CG2
VAL
A
597
80.347
−66.701
60.518
1.00
32.40


ATOM
445
N
GLU
A
598
81.644
−69.746
58.869
1.00
33.94


ATOM
446
CA
GLU
A
598
82.543
−69.739
57.732
1.00
34.87


ATOM
447
C
GLU
A
598
82.148
−68.523
56.908
1.00
35.39


ATOM
448
O
GLU
A
598
81.043
−68.007
57.051
1.00
35.36


ATOM
449
CB
GLU
A
598
82.360
−71.012
56.904
1.00
35.00


ATOM
450
CG
GLU
A
598
83.528
−71.336
55.992
1.00
35.35


ATOM
451
CD
GLU
A
598
83.194
−72.435
54.996
1.00
35.55


ATOM
452
OE1
GLU
A
598
82.464
−72.150
54.020
1.00
35.67


ATOM
453
OE2
GLU
A
598
83.652
−73.580
55.189
1.00
35.63


ATOM
454
N
ALA
A
599
83.058
−68.054
56.066
1.00
36.17


ATOM
455
CA
ALA
A
599
82.787
−66.907
55.215
1.00
37.00


ATOM
456
C
ALA
A
599
83.974
−66.706
54.295
1.00
37.65


ATOM
457
O
ALA
A
599
85.050
−67.251
54.530
1.00
37.69


ATOM
458
CB
ALA
A
599
82.556
−65.662
56.061
1.00
36.91


ATOM
459
N
THR
A
600
83.770
−65.944
53.230
1.00
38.50


ATOM
460
CA
THR
A
600
84.848
−65.664
52.294
1.00
39.39


ATOM
461
C
THR
A
600
85.191
−64.189
52.438
1.00
39.97


ATOM
462
O
THR
A
600
84.303
−63.338
52.501
1.00
39.98


ATOM
463
CB
THR
A
600
84.436
−65.969
50.833
1.00
39.39


ATOM
464
OG1
THR
A
600
83.192
−65.323
50.540
1.00
39.58


ATOM
465
CG2
THR
A
600
84.292
−67.474
50.620
1.00
39.42


ATOM
466
N
ALA
A
601
86.484
−63.899
52.512
1.00
40.75


ATOM
467
CA
ALA
A
601
86.955
−62.529
52.670
1.00
41.63


ATOM
468
C
ALA
A
601
87.458
−61.922
51.358
1.00
42.22


ATOM
469
O
ALA
A
601
88.433
−62.397
50.774
1.00
42.29


ATOM
470
CB
ALA
A
601
88.058
−62.482
53.721
1.00
41.53


ATOM
471
N
PHE
A
602
86.783
−60.864
50.917
1.00
42.96


ATOM
472
CA
PHE
A
602
87.135
−60.150
49.691
1.00
43.78


ATOM
473
C
PHE
A
602
87.840
−58.841
50.025
1.00
44.20


ATOM
474
O
PHE
A
602
87.269
−57.973
50.684
1.00
44.26


ATOM
475
CB
PHE
A
602
85.888
−59.811
48.871
1.00
43.97


ATOM
476
CG
PHE
A
602
85.094
−61.006
48.446
1.00
44.28


ATOM
477
CD1
PHE
A
602
83.981
−61.411
49.175
1.00
44.40


ATOM
478
CD2
PHE
A
602
85.455
−61.725
47.311
1.00
44.38


ATOM
479
CE1
PHE
A
602
83.234
−62.516
48.782
1.00
44.49


ATOM
480
CE2
PHE
A
602
84.715
−62.834
46.909
1.00
44.51


ATOM
481
CZ
PHE
A
602
83.601
−63.226
47.648
1.00
44.52


ATOM
482
N
GLY
A
603
89.073
−58.696
49.557
1.00
44.71


ATOM
483
CA
GLY
A
603
89.806
−57.472
49.816
1.00
45.42


ATOM
484
C
GLY
A
603
90.488
−57.472
51.167
1.00
45.88


ATOM
485
O
GLY
A
603
90.668
−56.420
51.781
1.00
45.94


ATOM
486
N
LEU
A
604
90.858
−58.660
51.631
1.00
46.38


ATOM
487
CA
LEU
A
604
91.539
−58.819
52.908
1.00
46.85


ATOM
488
C
LEU
A
604
92.974
−59.240
52.621
1.00
47.15


ATOM
489
O
LEU
A
604
93.213
−60.272
51.989
1.00
47.20


ATOM
490
CB
LEU
A
604
90.837
−59.888
53.754
1.00
46.90


ATOM
491
CG
LEU
A
604
91.311
−60.096
55.197
1.00
46.97


ATOM
492
CD1
LEU
A
604
90.336
−61.012
55.916
1.00
47.02


ATOM
493
CD2
LEU
A
604
92.710
−60.686
55.218
1.00
47.03


ATOM
494
N
GLY
A
605
93.925
−58.436
53.085
1.00
47.50


ATOM
495
CA
GLY
A
605
95.326
−58.742
52.861
1.00
47.91


ATOM
496
C
GLY
A
605
95.911
−57.958
51.701
1.00
48.18


ATOM
497
O
GLY
A
605
97.130
−57.820
51.593
1.00
48.23


ATOM
498
N
LYS
A
606
95.046
−57.445
50.829
1.00
48.43


ATOM
499
CA
LYS
A
606
95.492
−56.673
49.673
1.00
48.69


ATOM
500
C
LYS
A
606
94.328
−56.114
48.856
1.00
48.80


ATOM
501
O
LYS
A
606
93.220
−55.942
49.365
1.00
48.89


ATOM
502
CB
LYS
A
606
96.378
−57.534
48.766
1.00
48.78


ATOM
503
CG
LYS
A
606
95.736
−58.841
48.335
1.00
48.86


ATOM
504
CD
LYS
A
606
96.431
−59.426
47.118
1.00
48.96


ATOM
505
CE
LYS
A
606
96.162
−58.585
45.877
1.00
49.07


ATOM
506
NZ
LYS
A
606
96.764
−59.174
44.645
1.00
49.13


ATOM
507
N
ALA
A
607
94.590
−55.835
47.582
1.00
48.89


ATOM
508
CA
ALA
A
607
93.578
−55.289
46.683
1.00
48.92


ATOM
509
C
ALA
A
607
92.264
−56.061
46.763
1.00
48.92


ATOM
510
O
ALA
A
607
91.190
−55.467
46.902
1.00
48.97


ATOM
511
CB
ALA
A
607
94.101
−55.298
45.243
1.00
48.97


ATOM
512
N
ASP
A
608
92.358
−57.385
46.674
1.00
48.81


ATOM
513
CA
ASP
A
608
91.183
−58.250
46.725
1.00
48.66


ATOM
514
C
ASP
A
608
91.639
−59.702
46.549
1.00
48.40


ATOM
515
O
ASP
A
608
91.367
−60.328
45.526
1.00
48.44


ATOM
516
CB
ASP
A
608
90.206
−57.842
45.612
1.00
48.87


ATOM
517
CG
ASP
A
608
88.871
−58.562
45.700
1.00
49.01


ATOM
518
OD1
ASP
A
608
88.838
−59.775
45.427
1.00
49.14


ATOM
519
OD2
ASP
A
608
87.854
−57.913
46.038
1.00
49.13


ATOM
520
N
ALA
A
609
92.333
−60.219
47.564
1.00
48.01


ATOM
521
CA
ALA
A
609
92.871
−61.583
47.562
1.00
47.59


ATOM
522
C
ALA
A
609
91.829
−62.704
47.527
1.00
47.24


ATOM
523
O
ALA
A
609
92.071
−63.758
46.942
1.00
47.24


ATOM
524
CB
ALA
A
609
93.790
−61.773
48.766
1.00
47.63


ATOM
525
N
VAL
A
610
90.684
−62.487
48.164
1.00
46.80


ATOM
526
CA
VAL
A
610
89.613
−63.488
48.182
1.00
46.25


ATOM
527
C
VAL
A
610
90.038
−64.836
48.769
1.00
45.79


ATOM
528
O
VAL
A
610
90.797
−65.586
48.151
1.00
45.80


ATOM
529
CB
VAL
A
610
89.075
−63.761
46.764
1.00
46.31


ATOM
530
CG1
VAL
A
610
87.715
−64.435
46.846
1.00
46.35


ATOM
531
CG2
VAL
A
610
88.986
−62.476
45.986
1.00
46.32


ATOM
532
N
LEU
A
611
89.539
−65.142
49.963
1.00
45.17


ATOM
533
CA
LEU
A
611
89.843
−66.407
50.625
1.00
44.44


ATOM
534
C
LEU
A
611
88.762
−66.765
51.634
1.00
43.81


ATOM
535
O
LEU
A
611
87.967
−65.917
52.036
1.00
43.73


ATOM
536
CB
LEU
A
611
91.210
−66.346
51.317
1.00
44.56


ATOM
537
CG
LEU
A
611
91.612
−65.047
52.019
1.00
44.66


ATOM
538
CD1
LEU
A
611
90.583
−64.666
53.058
1.00
44.66


ATOM
539
CD2
LEU
A
611
92.985
−65.226
52.662
1.00
44.71


ATOM
540
N
LYS
A
612
88.723
−68.031
52.030
1.00
43.05


ATOM
541
CA
LYS
A
612
87.728
−68.466
52.995
1.00
42.19


ATOM
542
C
LYS
A
612
88.330
−68.318
54.382
1.00
41.42


ATOM
543
O
LYS
A
612
89.493
−68.643
54.603
1.00
41.31


ATOM
544
CB
LYS
A
612
87.310
−69.917
52.728
1.00
42.35


ATOM
545
CG
LYS
A
612
86.143
−70.368
53.594
1.00
42.49


ATOM
546
CD
LYS
A
612
85.360
−71.510
52.967
1.00
42.66


ATOM
547
CE
LYS
A
612
86.176
−72.791
52.871
1.00
42.77


ATOM
548
NZ
LYS
A
612
85.352
−73.920
52.340
1.00
42.77


ATOM
549
N
VAL
A
613
87.530
−67.808
55.310
1.00
40.59


ATOM
550
CA
VAL
A
613
87.988
−67.585
56.673
1.00
39.70


ATOM
551
C
VAL
A
613
86.958
−68.012
57.715
1.00
39.11


ATOM
552
O
VAL
A
613
85.838
−68.403
57.383
1.00
38.96


ATOM
553
CB
VAL
A
613
88.299
−66.092
56.897
1.00
39.66


ATOM
554
CG1
VAL
A
613
89.397
−65.641
55.963
1.00
39.57


ATOM
555
CG2
VAL
A
613
87.045
−65.265
56.669
1.00
39.56


ATOM
556
N
ALA
A
614
87.362
−67.929
58.978
1.00
38.40


ATOM
557
CA
ALA
A
614
86.499
−68.267
60.101
1.00
37.73


ATOM
558
C
ALA
A
614
86.249
−66.981
60.874
1.00
37.28


ATOM
559
O
ALA
A
614
87.185
−66.245
61.177
1.00
37.13


ATOM
560
CB
ALA
A
614
87.176
−69.289
60.994
1.00
37.69


ATOM
561
N
VAL
A
615
84.989
−66.706
61.188
1.00
36.75


ATOM
562
CA
VAL
A
615
84.643
−65.496
61.919
1.00
36.29


ATOM
563
C
VAL
A
615
83.986
−65.815
63.254
1.00
36.10


ATOM
564
O
VAL
A
615
82.931
−66.450
63.300
1.00
35.95


ATOM
565
CB
VAL
A
615
83.673
−64.606
61.105
1.00
36.20


ATOM
566
CG1
VAL
A
615
83.362
−63.337
61.878
1.00
36.07


ATOM
567
CG2
VAL
A
615
84.275
−64.271
59.751
1.00
36.14


ATOM
568
N
LYS
A
616
84.615
−65.382
64.342
1.00
35.89


ATOM
569
CA
LYS
A
616
84.052
−65.608
65.664
1.00
35.73


ATOM
570
C
LYS
A
616
83.322
−64.345
66.095
1.00
35.68


ATOM
571
O
LYS
A
616
83.802
−63.235
65.875
1.00
35.68


ATOM
572
CB
LYS
A
616
85.142
−65.968
66.685
1.00
35.66


ATOM
573
CG
LYS
A
616
84.612
−66.018
68.123
1.00
35.65


ATOM
574
CD
LYS
A
616
85.302
−67.054
69.016
1.00
35.54


ATOM
575
CE
LYS
A
616
86.754
−66.736
69.272
1.00
35.58


ATOM
576
NZ
LYS
A
616
87.297
−67.521
70.419
1.00
35.32


ATOM
577
N
MET
A
617
82.154
−64.524
66.699
1.00
35.61


ATOM
578
CA
MET
A
617
81.336
−63.407
67.158
1.00
35.66


ATOM
579
C
MET
A
617
80.531
−63.849
68.372
1.00
35.74


ATOM
580
O
MET
A
617
80.343
−65.042
68.596
1.00
35.63


ATOM
581
CB
MET
A
617
80.379
−62.978
66.044
1.00
35.56


ATOM
582
CG
MET
A
617
79.450
−64.104
65.588
1.00
35.42


ATOM
583
SD
MET
A
617
78.592
−63.742
64.053
1.00
35.28


ATOM
584
CE
MET
A
617
79.884
−64.074
62.855
1.00
35.30


ATOM
585
N
LEU
A
618
80.059
−62.891
69.158
1.00
35.91


ATOM
586
CA
LEU
A
618
79.258
−63.224
70.327
1.00
36.21


ATOM
587
C
LEU
A
618
77.873
−63.660
69.868
1.00
36.48


ATOM
588
O
LEU
A
618
77.430
−63.291
68.783
1.00
36.44


ATOM
589
CB
LEU
A
618
79.122
−62.017
71.258
1.00
36.04


ATOM
590
CG
LEU
A
618
80.370
−61.524
71.988
1.00
35.97


ATOM
591
CD1
LEU
A
618
79.995
−60.378
72.920
1.00
35.87


ATOM
592
CD2
LEU
A
618
80.987
−62.665
72.775
1.00
35.81


ATOM
593
N
LYS
A
619
77.201
−64.462
70.684
1.00
36.88


ATOM
594
CA
LYS
A
619
75.853
−64.894
70.350
1.00
37.35


ATOM
595
C
LYS
A
619
74.933
−63.746
70.750
1.00
37.68


ATOM
596
O
LYS
A
619
73.955
−63.458
70.066
1.00
37.71


ATOM
597
CB
LYS
A
619
75.480
−66.172
71.110
1.00
37.25


ATOM
598
CG
LYS
A
619
76.358
−67.358
70.766
1.00
37.25


ATOM
599
CD
LYS
A
619
75.641
−68.685
70.973
1.00
37.26


ATOM
600
CE
LYS
A
619
75.331
−68.942
72.431
1.00
37.23


ATOM
601
NZ
LYS
A
619
74.619
−70.240
72.600
1.00
37.22


ATOM
602
N
SER
A
620
75.273
−63.086
71.857
1.00
38.19


ATOM
603
CA
SER
A
620
74.509
−61.945
72.370
1.00
38.68


ATOM
604
C
SER
A
620
75.422
−60.853
72.934
1.00
39.01


ATOM
605
O
SER
A
620
76.350
−61.139
73.697
1.00
39.06


ATOM
606
CB
SER
A
620
73.542
−62.394
73.465
1.00
38.72


ATOM
607
OG
SER
A
620
72.982
−61.271
74.127
1.00
38.83


ATOM
608
N
THR
A
621
75.157
−59.601
72.561
1.00
39.36


ATOM
609
CA
THR
A
621
75.960
−58.479
73.045
1.00
39.68


ATOM
610
C
THR
A
621
75.351
−57.884
74.316
1.00
39.81


ATOM
611
O
THR
A
621
75.638
−56.744
74.685
1.00
39.89


ATOM
612
CB
THR
A
621
76.085
−57.364
71.973
1.00
39.76


ATOM
613
OG1
THR
A
621
74.806
−56.751
71.750
1.00
39.92


ATOM
614
CG2
THR
A
621
76.593
−57.947
70.660
1.00
39.84


ATOM
615
N
ALA
A
622
74.520
−58.672
74.992
1.00
39.92


ATOM
616
CA
ALA
A
622
73.866
−58.224
76.214
1.00
39.99


ATOM
617
C
ALA
A
622
74.837
−57.938
77.357
1.00
40.09


ATOM
618
O
ALA
A
622
74.811
−56.854
77.945
1.00
40.12


ATOM
619
CB
ALA
A
622
72.850
−59.256
76.658
1.00
40.04


ATOM
620
N
HIS
A
623
75.696
−58.906
77.666
1.00
40.12


ATOM
621
CA
HIS
A
623
76.646
−58.758
78.766
1.00
40.11


ATOM
622
C
HIS
A
623
77.975
−58.114
78.384
1.00
39.94


ATOM
623
O
HIS
A
623
78.738
−58.651
77.581
1.00
39.94


ATOM
624
CB
HIS
A
623
76.893
−60.122
79.414
1.00
40.37


ATOM
625
CG
HIS
A
623
75.657
−60.748
79.982
1.00
40.65


ATOM
626
ND1
HIS
A
623
74.515
−60.946
79.236
1.00
40.76


ATOM
627
CD2
HIS
A
623
75.382
−61.217
81.223
1.00
40.78


ATOM
628
CE1
HIS
A
623
73.590
−61.511
79.992
1.00
40.83


ATOM
629
NE2
HIS
A
623
74.090
−61.686
81.202
1.00
40.86


ATOM
630
N
ALA
A
624
78.249
−56.958
78.982
1.00
39.68


ATOM
631
CA
ALA
A
624
79.481
−56.228
78.709
1.00
39.39


ATOM
632
C
ALA
A
624
80.727
−57.065
78.986
1.00
39.13


ATOM
633
O
ALA
A
624
81.736
−56.938
78.291
1.00
39.14


ATOM
634
CB
ALA
A
624
79.518
−54.946
79.533
1.00
39.46


ATOM
635
N
ASP
A
625
80.663
−57.918
80.000
1.00
38.80


ATOM
636
CA
ASP
A
625
81.808
−58.751
80.333
1.00
38.44


ATOM
637
C
ASP
A
625
82.092
−59.730
79.193
1.00
38.04


ATOM
638
O
ASP
A
625
83.245
−60.063
78.928
1.00
38.01


ATOM
639
CB
ASP
A
625
81.566
−59.499
81.654
1.00
38.63


ATOM
640
CG
ASP
A
625
80.518
−60.588
81.536
1.00
38.79


ATOM
641
OD1
ASP
A
625
79.395
−60.304
81.066
1.00
39.01


ATOM
642
OD2
ASP
A
625
80.820
−61.733
81.930
1.00
38.94


ATOM
643
N
GLU
A
626
81.039
−60.178
78.514
1.00
37.56


ATOM
644
CA
GLU
A
626
81.197
−61.094
77.391
1.00
36.99


ATOM
645
C
GLU
A
626
81.783
−60.336
76.201
1.00
36.51


ATOM
646
O
GLU
A
626
82.567
−60.886
75.425
1.00
36.42


ATOM
647
CB
GLU
A
626
79.850
−61.712
77.009
1.00
37.10


ATOM
648
CG
GLU
A
626
79.208
−62.507
78.137
1.00
37.26


ATOM
649
CD
GLU
A
626
77.945
−63.232
77.716
1.00
37.33


ATOM
650
OE1
GLU
A
626
77.290
−63.832
78.596
1.00
37.34


ATOM
651
OE2
GLU
A
626
77.610
−63.206
76.512
1.00
37.39


ATOM
652
N
LYS
A
627
81.399
−59.068
76.064
1.00
35.85


ATOM
653
CA
LYS
A
627
81.900
−58.239
74.973
1.00
35.17


ATOM
654
C
LYS
A
627
83.372
−57.920
75.191
1.00
34.62


ATOM
655
O
LYS
A
627
84.148
−57.872
74.239
1.00
34.55


ATOM
656
CB
LYS
A
627
81.097
−56.936
74.868
1.00
35.33


ATOM
657
CG
LYS
A
627
79.686
−57.125
74.323
1.00
35.44


ATOM
658
CD
LYS
A
627
78.911
−55.808
74.229
1.00
35.58


ATOM
659
CE
LYS
A
627
78.497
−55.295
75.604
1.00
35.74


ATOM
660
NZ
LYS
A
627
77.567
−54.122
75.516
1.00
35.91


ATOM
661
N
GLU
A
628
83.759
−57.704
76.445
1.00
33.92


ATOM
662
CA
GLU
A
628
85.148
−57.393
76.744
1.00
33.26


ATOM
663
C
GLU
A
628
86.013
−58.647
76.622
1.00
32.59


ATOM
664
O
GLU
A
628
87.214
−58.558
76.372
1.00
32.46


ATOM
665
CB
GLU
A
628
85.279
−56.796
78.151
1.00
33.59


ATOM
666
CG
GLU
A
628
86.697
−56.316
78.484
1.00
34.00


ATOM
667
CD
GLU
A
628
87.320
−55.480
77.365
1.00
34.25


ATOM
668
OE1
GLU
A
628
86.697
−54.478
76.941
1.00
34.34


ATOM
669
OE2
GLU
A
628
88.438
−55.826
76.909
1.00
34.45


ATOM
670
N
ALA
A
629
85.392
−59.810
76.794
1.00
31.73


ATOM
671
CA
ALA
A
629
86.105
−61.079
76.686
1.00
30.91


ATOM
672
C
ALA
A
629
86.567
−61.271
75.245
1.00
30.32


ATOM
673
O
ALA
A
629
87.712
−61.662
74.993
1.00
30.23


ATOM
674
CB
ALA
A
629
85.194
−62.233
77.105
1.00
30.91


ATOM
675
N
LEU
A
630
85.670
−60.991
74.302
1.00
29.61


ATOM
676
CA
LEU
A
630
85.991
−61.125
72.887
1.00
28.88


ATOM
677
C
LEU
A
630
87.097
−60.145
72.512
1.00
28.48


ATOM
678
O
LEU
A
630
87.997
−60.490
71.744
1.00
28.45


ATOM
679
CB
LEU
A
630
84.750
−60.874
72.022
1.00
28.73


ATOM
680
CG
LEU
A
630
84.940
−61.144
70.526
1.00
28.59


ATOM
681
CD1
LEU
A
630
85.321
−62.603
70.316
1.00
28.58


ATOM
682
CD2
LEU
A
630
83.661
−60.813
69.767
1.00
28.47


ATOM
683
N
MET
A
631
87.032
−58.925
73.047
1.00
28.01


ATOM
684
CA
MET
A
631
88.062
−57.923
72.766
1.00
27.59


ATOM
685
C
MET
A
631
89.417
−58.370
73.314
1.00
27.25


ATOM
686
O
MET
A
631
90.448
−58.189
72.660
1.00
27.11


ATOM
687
CB
MET
A
631
87.693
−56.560
73.369
1.00
27.78


ATOM
688
CG
MET
A
631
86.659
−55.764
72.568
1.00
27.90


ATOM
689
SD
MET
A
631
87.094
−55.583
70.812
1.00
28.18


ATOM
690
CE
MET
A
631
88.568
−54.526
70.900
1.00
28.00


ATOM
691
N
SER
A
632
89.412
−58.946
74.515
1.00
26.88


ATOM
692
CA
SER
A
632
90.648
−59.427
75.134
1.00
26.51


ATOM
693
C
SER
A
632
91.263
−60.536
74.289
1.00
26.00


ATOM
694
O
SER
A
632
92.472
−60.543
74.054
1.00
25.94


ATOM
695
CB
SER
A
632
90.385
−59.956
76.549
1.00
26.75


ATOM
696
OG
SER
A
632
90.092
−58.904
77.457
1.00
27.17


ATOM
697
N
GLU
A
633
90.436
−61.482
73.846
1.00
25.41


ATOM
698
CA
GLU
A
633
90.932
−62.569
73.010
1.00
24.84


ATOM
699
C
GLU
A
633
91.583
−61.963
71.780
1.00
24.56


ATOM
700
O
GLU
A
633
92.680
−62.350
71.389
1.00
24.29


ATOM
701
CB
GLU
A
633
89.799
−63.486
72.540
1.00
24.71


ATOM
702
CG
GLU
A
633
89.203
−64.393
73.591
1.00
24.53


ATOM
703
CD
GLU
A
633
88.283
−65.429
72.969
1.00
24.42


ATOM
704
OE1
GLU
A
633
87.756
−66.276
73.705
1.00
24.37


ATOM
705
OE2
GLU
A
633
88.090
−65.390
71.733
1.00
24.33


ATOM
706
N
LEU
A
634
90.886
−61.009
71.170
1.00
24.35


ATOM
707
CA
LEU
A
634
91.377
−60.344
69.969
1.00
24.28


ATOM
708
C
LEU
A
634
92.720
−59.665
70.227
1.00
24.40


ATOM
709
O
LEU
A
634
93.668
−59.827
69.454
1.00
24.27


ATOM
710
CB
LEU
A
634
90.350
−59.305
69.488
1.00
24.00


ATOM
711
CG
LEU
A
634
90.747
−58.355
68.348
1.00
23.83


ATOM
712
CD1
LEU
A
634
91.180
−59.129
67.124
1.00
23.56


ATOM
713
CD2
LEU
A
634
89.561
−57.445
68.015
1.00
23.68


ATOM
714
N
LYS
A
635
92.797
−58.920
71.325
1.00
24.66


ATOM
715
CA
LYS
A
635
94.027
−58.199
71.667
1.00
24.96


ATOM
716
C
LYS
A
635
95.236
−59.111
71.835
1.00
25.03


ATOM
717
O
LYS
A
635
96.346
−58.775
71.412
1.00
24.99


ATOM
718
CB
LYS
A
635
93.818
−57.378
72.941
1.00
25.11


ATOM
719
CG
LYS
A
635
92.836
−56.235
72.781
1.00
25.42


ATOM
720
CD
LYS
A
635
92.764
−55.419
74.056
1.00
25.79


ATOM
721
CE
LYS
A
635
91.785
−54.267
73.935
1.00
26.08


ATOM
722
NZ
LYS
A
635
91.693
−53.535
75.237
1.00
26.35


ATOM
723
N
ILE
A
636
95.025
−60.263
72.460
1.00
25.15


ATOM
724
CA
ILE
A
636
96.114
−61.211
72.664
1.00
25.25


ATOM
725
C
ILE
A
636
96.490
−61.865
71.341
1.00
25.36


ATOM
726
O
ILE
A
636
97.669
−61.942
70.989
1.00
25.33


ATOM
727
CB
ILE
A
636
95.719
−62.272
73.716
1.00
25.30


ATOM
728
CG1
ILE
A
636
95.695
−61.614
75.102
1.00
25.35


ATOM
729
CG2
ILE
A
636
96.703
−63.440
73.691
1.00
25.29


ATOM
730
CD1
ILE
A
636
95.069
−62.440
76.180
1.00
25.41


ATOM
731
N
MET
A
637
95.495
−62.332
70.599
1.00
25.51


ATOM
732
CA
MET
A
637
95.772
−62.950
69.307
1.00
25.73


ATOM
733
C
MET
A
637
96.510
−61.950
68.420
1.00
25.98


ATOM
734
O
MET
A
637
97.405
−62.326
67.658
1.00
26.02


ATOM
735
CB
MET
A
637
94.469
−63.410
68.651
1.00
25.60


ATOM
736
CG
MET
A
637
93.868
−64.626
69.325
1.00
25.35


ATOM
737
SD
MET
A
637
92.163
−64.952
68.847
1.00
25.11


ATOM
738
CE
MET
A
637
92.354
−65.159
67.093
1.00
24.99


ATOM
739
N
SER
A
638
96.146
−60.675
68.531
1.00
26.22


ATOM
740
CA
SER
A
638
96.809
−59.633
67.753
1.00
26.65


ATOM
741
C
SER
A
638
98.283
−59.582
68.133
1.00
26.85


ATOM
742
O
SER
A
638
99.166
−59.618
67.278
1.00
26.84


ATOM
743
CB
SER
A
638
96.194
−58.262
68.040
1.00
26.66


ATOM
744
OG
SER
A
638
94.896
−58.150
67.497
1.00
26.93


ATOM
745
N
HIS
A
639
98.525
−59.493
69.434
1.00
27.16


ATOM
746
CA
HIS
A
639
99.871
−59.421
69.989
1.00
27.52


ATOM
747
C
HIS
A
639
100.769
−60.597
69.621
1.00
27.71


ATOM
748
O
HIS
A
639
101.950
−60.419
69.319
1.00
27.71


ATOM
749
CB
HIS
A
639
99.778
−59.325
71.513
1.00
27.61


ATOM
750
CG
HIS
A
639
101.105
−59.337
72.202
1.00
27.81


ATOM
751
ND1
HIS
A
639
101.955
−58.252
72.198
1.00
27.83


ATOM
752
CD2
HIS
A
639
101.737
−60.309
72.902
1.00
27.86


ATOM
753
CE1
HIS
A
639
103.053
−58.555
72.868
1.00
27.99


ATOM
754
NE2
HIS
A
639
102.946
−59.797
73.305
1.00
27.88


ATOM
755
N
LEU
A
640
100.207
−61.799
69.654
1.00
27.93


ATOM
756
CA
LEU
A
640
100.964
−63.010
69.368
1.00
28.18


ATOM
757
C
LEU
A
640
101.793
−63.014
68.099
1.00
28.30


ATOM
758
O
LEU
A
640
102.939
−63.452
68.109
1.00
28.37


ATOM
759
CB
LEU
A
640
100.030
−64.222
69.362
1.00
28.19


ATOM
760
CG
LEU
A
640
99.553
−64.674
70.744
1.00
28.24


ATOM
761
CD1
LEU
A
640
98.666
−65.890
70.586
1.00
28.44


ATOM
762
CD2
LEU
A
640
100.750
−65.009
71.632
1.00
28.36


ATOM
763
N
GLY
A
641
101.218
−62.536
67.004
1.00
28.48


ATOM
764
CA
GLY
A
641
101.947
−62.534
65.753
1.00
28.59


ATOM
765
C
GLY
A
641
101.568
−63.764
64.952
1.00
28.67


ATOM
766
O
GLY
A
641
100.780
−64.593
65.415
1.00
28.64


ATOM
767
N
GLN
A
642
102.133
−63.889
63.756
1.00
28.67


ATOM
768
CA
GLN
A
642
101.837
−65.015
62.885
1.00
28.62


ATOM
769
C
GLN
A
642
102.839
−66.154
63.014
1.00
28.34


ATOM
770
O
GLN
A
642
104.027
−65.934
63.240
1.00
28.26


ATOM
771
CB
GLN
A
642
101.792
−64.532
61.429
1.00
29.03


ATOM
772
CG
GLN
A
642
101.419
−65.598
60.405
1.00
29.59


ATOM
773
CD
GLN
A
642
102.556
−66.565
60.092
1.00
29.90


ATOM
774
OE1
GLN
A
642
102.320
−67.696
59.649
1.00
30.04


ATOM
775
NE2
GLN
A
642
103.796
−66.120
60.308
1.00
30.10


ATOM
776
N
HIS
A
643
102.342
−67.381
62.888
1.00
28.01


ATOM
777
CA
HIS
A
643
103.194
−68.562
62.926
1.00
27.70


ATOM
778
C
HIS
A
643
102.492
−69.708
62.220
1.00
27.57


ATOM
779
O
HIS
A
643
101.267
−69.846
62.288
1.00
27.54


ATOM
780
CB
HIS
A
643
103.558
−68.975
64.354
1.00
27.58


ATOM
781
CG
HIS
A
643
104.595
−70.058
64.412
1.00
27.41


ATOM
782
ND1
HIS
A
643
104.296
−71.388
64.205
1.00
27.40


ATOM
783
CD2
HIS
A
643
105.938
−70.000
64.589
1.00
27.35


ATOM
784
CE1
HIS
A
643
105.408
−72.102
64.251
1.00
27.34


ATOM
785
NE2
HIS
A
643
106.419
−71.283
64.482
1.00
27.32


ATOM
786
N
GLU
A
644
103.290
−70.523
61.548
1.00
27.34


ATOM
787
CA
GLU
A
644
102.809
−71.654
60.771
1.00
27.29


ATOM
788
C
GLU
A
644
102.013
−72.689
61.552
1.00
26.80


ATOM
789
O
GLU
A
644
101.121
−73.332
60.992
1.00
26.74


ATOM
790
CB
GLU
A
644
104.009
−72.324
60.088
1.00
27.80


ATOM
791
CG
GLU
A
644
103.727
−73.645
59.394
1.00
28.62


ATOM
792
CD
GLU
A
644
102.954
−73.493
58.101
1.00
29.09


ATOM
793
OE1
GLU
A
644
102.806
−74.515
57.384
1.00
29.45


ATOM
794
OE2
GLU
A
644
102.498
−72.364
57.798
1.00
29.50


ATOM
795
N
ASN
A
645
102.312
−72.841
62.841
1.00
26.16


ATOM
796
CA
ASN
A
645
101.622
−73.846
63.635
1.00
25.62


ATOM
797
C
ASN
A
645
100.643
−73.389
64.721
1.00
25.27


ATOM
798
O
ASN
A
645
100.449
−74.074
65.723
1.00
25.15


ATOM
799
CB
ASN
A
645
102.644
−74.837
64.204
1.00
25.29


ATOM
800
CG
ASN
A
645
103.453
−75.533
63.107
1.00
25.33


ATOM
801
OD1
ASN
A
645
104.657
−75.298
62.961
1.00
24.96


ATOM
802
ND2
ASN
A
645
102.788
−76.390
62.326
1.00
24.99


ATOM
803
N
ILE
A
646
100.039
−72.223
64.523
1.00
25.00


ATOM
804
CA
ILE
A
646
99.001
−71.738
65.429
1.00
24.83


ATOM
805
C
ILE
A
646
97.899
−71.246
64.493
1.00
24.64


ATOM
806
O
ILE
A
646
98.157
−71.008
63.313
1.00
24.43


ATOM
807
CB
ILE
A
646
99.448
−70.550
66.345
1.00
24.75


ATOM
808
CG1
ILE
A
646
99.716
−69.300
65.508
1.00
24.81


ATOM
809
CG2
ILE
A
646
100.677
−70.941
67.162
1.00
24.69


ATOM
810
CD1
ILE
A
646
99.865
−68.037
66.343
1.00
24.83


ATOM
811
N
VAL
A
647
96.675
−71.130
65.003
1.00
24.54


ATOM
812
CA
VAL
A
647
95.563
−70.636
64.194
1.00
24.69


ATOM
813
C
VAL
A
647
95.704
−69.117
64.204
1.00
24.69


ATOM
814
O
VAL
A
647
95.538
−68.482
65.248
1.00
24.60


ATOM
815
CB
VAL
A
647
94.199
−71.033
64.799
1.00
24.52


ATOM
816
CG1
VAL
A
647
93.072
−70.487
63.942
1.00
24.55


ATOM
817
CG2
VAL
A
647
94.100
−72.543
64.901
1.00
24.58


ATOM
818
N
ASN
A
648
96.001
−68.547
63.037
1.00
24.83


ATOM
819
CA
ASN
A
648
96.244
−67.113
62.906
1.00
25.05


ATOM
820
C
ASN
A
648
95.082
−66.146
62.743
1.00
25.13


ATOM
821
O
ASN
A
648
94.064
−66.449
62.123
1.00
25.12


ATOM
822
CB
ASN
A
648
97.222
−66.861
61.749
1.00
25.25


ATOM
823
CG
ASN
A
648
98.587
−67.449
62.002
1.00
25.23


ATOM
824
OD1
ASN
A
648
99.284
−67.051
62.936
1.00
25.51


ATOM
825
ND2
ASN
A
648
98.980
−68.404
61.176
1.00
25.36


ATOM
826
N
LEU
A
649
95.270
−64.961
63.314
1.00
25.21


ATOM
827
CA
LEU
A
649
94.309
−63.879
63.215
1.00
25.36


ATOM
828
C
LEU
A
649
94.561
−63.263
61.843
1.00
25.51


ATOM
829
O
LEU
A
649
95.708
−63.229
61.378
1.00
25.49


ATOM
830
CB
LEU
A
649
94.576
−62.831
64.294
1.00
25.41


ATOM
831
CG
LEU
A
649
93.784
−61.523
64.208
1.00
25.38


ATOM
832
CD1
LEU
A
649
92.307
−61.772
64.487
1.00
25.35


ATOM
833
CD2
LEU
A
649
94.351
−60.539
65.216
1.00
25.25


ATOM
834
N
LEU
A
650
93.502
−62.769
61.206
1.00
25.58


ATOM
835
CA
LEU
A
650
93.614
−62.165
59.887
1.00
25.65


ATOM
836
C
LEU
A
650
93.070
−60.751
59.879
1.00
25.71


ATOM
837
O
LEU
A
650
93.524
−59.904
59.111
1.00
25.72


ATOM
838
CB
LEU
A
650
92.861
−63.008
58.849
1.00
25.75


ATOM
839
CG
LEU
A
650
93.388
−64.419
58.569
1.00
25.83


ATOM
840
CD1
LEU
A
650
92.438
−65.136
57.611
1.00
25.92


ATOM
841
CD2
LEU
A
650
94.787
−64.337
57.978
1.00
25.84


ATOM
842
N
GLY
A
651
92.089
−60.496
60.736
1.00
25.77


ATOM
843
CA
GLY
A
651
91.508
−59.171
60.804
1.00
25.94


ATOM
844
C
GLY
A
651
90.369
−59.125
61.793
1.00
26.06


ATOM
845
O
GLY
A
651
90.100
−60.110
62.477
1.00
25.99


ATOM
846
N
ALA
A
652
89.696
−57.984
61.869
1.00
26.26


ATOM
847
CA
ALA
A
652
88.580
−57.839
62.785
1.00
26.59


ATOM
848
C
ALA
A
652
87.677
−56.676
62.399
1.00
26.83


ATOM
849
O
ALA
A
652
88.109
−55.728
61.740
1.00
26.87


ATOM
850
CB
ALA
A
652
89.096
−57.650
64.208
1.00
26.40


ATOM
851
N
CYS
A
653
86.420
−56.765
62.816
1.00
27.19


ATOM
852
CA
CYS
A
653
85.438
−55.722
62.551
1.00
27.64


ATOM
853
C
CYS
A
653
84.960
−55.235
63.915
1.00
27.98


ATOM
854
O
CYS
A
653
84.154
−55.894
64.572
1.00
28.00


ATOM
855
CB
CYS
A
653
84.272
−56.294
61.736
1.00
27.63


ATOM
856
SG
CYS
A
653
84.775
−57.075
60.170
1.00
27.82


ATOM
857
N
THR
A
654
85.463
−54.083
64.350
1.00
28.35


ATOM
858
CA
THR
A
654
85.083
−53.567
65.658
1.00
28.73


ATOM
859
C
THR
A
654
84.234
−52.304
65.595
1.00
29.01


ATOM
860
O
THR
A
654
83.757
−51.831
66.625
1.00
29.11


ATOM
861
CB
THR
A
654
86.331
−53.260
66.524
1.00
28.74


ATOM
862
OG1
THR
A
654
87.022
−52.126
65.987
1.00
28.85


ATOM
863
CG2
THR
A
654
87.286
−54.449
66.528
1.00
28.79


ATOM
864
N
HIS
A
655
84.039
−51.765
64.395
1.00
29.24


ATOM
865
CA
HIS
A
655
83.258
−50.536
64.241
1.00
29.53


ATOM
866
C
HIS
A
655
81.931
−50.720
63.504
1.00
29.59


ATOM
867
O
HIS
A
655
81.835
−51.516
62.568
1.00
29.68


ATOM
868
CB
HIS
A
655
84.088
−49.477
63.502
1.00
29.59


ATOM
869
CG
HIS
A
655
85.350
−49.093
64.209
1.00
29.73


ATOM
870
ND1
HIS
A
655
85.357
−48.524
65.464
1.00
29.88


ATOM
871
CD2
HIS
A
655
86.648
−49.200
63.837
1.00
29.80


ATOM
872
CE1
HIS
A
655
86.604
−48.296
65.836
1.00
29.87


ATOM
873
NE2
HIS
A
655
87.408
−48.697
64.866
1.00
29.88


ATOM
874
N
GLY
A
656
80.922
−49.969
63.943
1.00
29.64


ATOM
875
CA
GLY
A
656
79.607
−49.998
63.327
1.00
29.65


ATOM
876
C
GLY
A
656
78.804
−51.276
63.433
1.00
29.63


ATOM
877
O
GLY
A
656
78.024
−51.590
62.535
1.00
29.68


ATOM
878
N
GLY
A
657
78.976
−52.005
64.531
1.00
29.60


ATOM
879
CA
GLY
A
657
78.258
−53.252
64.716
1.00
29.48


ATOM
880
C
GLY
A
657
79.035
−54.193
65.621
1.00
29.37


ATOM
881
O
GLY
A
657
80.160
−53.880
66.013
1.00
29.37


ATOM
882
N
PRO
A
658
78.466
−55.357
65.967
1.00
29.26


ATOM
883
CA
PRO
A
658
79.125
−56.337
66.834
1.00
29.05


ATOM
884
C
PRO
A
658
80.561
−56.630
66.398
1.00
28.76


ATOM
885
O
PRO
A
658
80.897
−56.554
65.212
1.00
28.76


ATOM
886
CB
PRO
A
658
78.229
−57.567
66.705
1.00
29.15


ATOM
887
CG
PRO
A
658
76.880
−56.969
66.496
1.00
29.33


ATOM
888
CD
PRO
A
658
77.174
−55.879
65.486
1.00
29.33


ATOM
889
N
VAL
A
659
81.400
−56.969
67.368
1.00
28.46


ATOM
890
CA
VAL
A
659
82.800
−57.283
67.108
1.00
28.17


ATOM
891
C
VAL
A
659
82.955
−58.634
66.415
1.00
27.80


ATOM
892
O
VAL
A
659
82.440
−59.647
66.885
1.00
27.81


ATOM
893
CB
VAL
A
659
83.607
−57.294
68.431
1.00
28.27


ATOM
894
CG1
VAL
A
659
85.027
−57.798
68.186
1.00
28.30


ATOM
895
CG2
VAL
A
659
83.634
−55.879
69.030
1.00
28.35


ATOM
896
N
LEU
A
660
83.658
−58.633
65.287
1.00
27.41


ATOM
897
CA
LEU
A
660
83.902
−59.852
64.526
1.00
27.06


ATOM
898
C
LEU
A
660
85.404
−60.097
64.493
1.00
26.83


ATOM
899
O
LEU
A
660
86.180
−59.187
64.201
1.00
26.77


ATOM
900
CB
LEU
A
660
83.393
−59.712
63.086
1.00
26.98


ATOM
901
CG
LEU
A
660
81.970
−59.193
62.856
1.00
26.93


ATOM
902
CD1
LEU
A
660
81.686
−59.186
61.358
1.00
26.78


ATOM
903
CD2
LEU
A
660
80.962
−60.058
63.587
1.00
26.89


ATOM
904
N
VAL
A
661
85.809
−61.327
64.799
1.00
26.48


ATOM
905
CA
VAL
A
661
87.219
−61.693
64.795
1.00
26.19


ATOM
906
C
VAL
A
661
87.432
−62.679
63.653
1.00
26.18


ATOM
907
O
VAL
A
661
86.835
−63.758
63.632
1.00
26.04


ATOM
908
CB
VAL
A
661
87.631
−62.335
66.140
1.00
26.10


ATOM
909
CG1
VAL
A
661
89.064
−62.817
66.076
1.00
25.83


ATOM
910
CG2
VAL
A
661
87.464
−61.323
67.261
1.00
25.92


ATOM
911
N
ILE
A
662
88.293
−62.296
62.712
1.00
26.11


ATOM
912
CA
ILE
A
662
88.567
−63.098
61.524
1.00
26.04


ATOM
913
C
ILE
A
662
89.866
−63.894
61.597
1.00
26.11


ATOM
914
O
ILE
A
662
90.946
−63.330
61.771
1.00
25.95


ATOM
915
CB
ILE
A
662
88.627
−62.192
60.279
1.00
26.13


ATOM
916
CG1
ILE
A
662
87.404
−61.272
60.252
1.00
26.15


ATOM
917
CG2
ILE
A
662
88.707
−63.040
59.018
1.00
26.07


ATOM
918
CD1
ILE
A
662
87.516
−60.143
59.250
1.00
26.13


ATOM
919
N
THR
A
663
89.752
−65.208
61.444
1.00
26.11


ATOM
920
CA
THR
A
663
90.909
−66.084
61.495
1.00
26.24


ATOM
921
C
THR
A
663
90.982
−66.949
60.251
1.00
26.38


ATOM
922
O
THR
A
663
90.038
−67.004
59.466
1.00
26.45


ATOM
923
CB
THR
A
663
90.866
−67.009
62.733
1.00
26.22


ATOM
924
OG1
THR
A
663
89.637
−67.748
62.741
1.00
26.28


ATOM
925
CG2
THR
A
663
90.966
−66.187
64.008
1.00
26.17


ATOM
926
N
GLU
A
664
92.111
−67.625
60.078
1.00
26.49


ATOM
927
CA
GLU
A
664
92.296
−68.496
58.932
1.00
26.68


ATOM
928
C
GLU
A
664
91.431
−69.746
59.094
1.00
26.67


ATOM
929
O
GLU
A
664
91.303
−70.297
60.189
1.00
26.70


ATOM
930
CB
GLU
A
664
93.767
−68.891
58.800
1.00
26.81


ATOM
931
CG
GLU
A
664
94.310
−69.677
59.971
1.00
27.18


ATOM
932
CD
GLU
A
664
95.771
−70.021
59.789
1.00
27.37


ATOM
933
OE1
GLU
A
664
96.121
−70.541
58.708
1.00
27.68


ATOM
934
OE2
GLU
A
664
96.568
−69.781
60.718
1.00
27.40


ATOM
935
N
TYR
A
665
90.832
−70.185
57.997
1.00
26.56


ATOM
936
CA
TYR
A
665
89.980
−71.365
58.017
1.00
26.44


ATOM
937
C
TYR
A
665
90.793
−72.657
57.889
1.00
26.34


ATOM
938
O
TYR
A
665
91.509
−72.841
56.908
1.00
26.35


ATOM
939
CB
TYR
A
665
88.974
−71.272
56.876
1.00
26.52


ATOM
940
CG
TYR
A
665
88.123
−72.507
56.721
1.00
26.57


ATOM
941
CD1
TYR
A
665
87.180
−72.849
57.694
1.00
26.53


ATOM
942
CD2
TYR
A
665
88.262
−73.339
55.613
1.00
26.47


ATOM
943
CE1
TYR
A
665
86.397
−73.987
57.565
1.00
26.47


ATOM
944
CE2
TYR
A
665
87.481
−74.488
55.478
1.00
26.50


ATOM
945
CZ
TYR
A
665
86.552
−74.799
56.461
1.00
26.39


ATOM
946
OH
TYR
A
665
85.776
−75.924
56.349
1.00
26.47


ATOM
947
N
CYS
A
666
90.690
−73.545
58.879
1.00
26.11


ATOM
948
CA
CYS
A
666
91.417
−74.824
58.853
1.00
25.93


ATOM
949
C
CYS
A
666
90.438
−75.925
58.425
1.00
25.97


ATOM
950
O
CYS
A
666
89.757
−76.522
59.251
1.00
25.96


ATOM
951
CB
CYS
A
666
91.996
−75.130
60.234
1.00
25.75


ATOM
952
SG
CYS
A
666
93.151
−73.866
60.841
1.00
25.34


ATOM
953
N
CYS
A
667
90.410
−76.193
57.122
1.00
25.92


ATOM
954
CA
CYS
A
667
89.483
−77.142
56.510
1.00
25.87


ATOM
955
C
CYS
A
667
89.189
−78.523
57.102
1.00
25.67


ATOM
956
O
CYS
A
667
88.085
−79.032
56.913
1.00
25.73


ATOM
957
CB
CYS
A
667
89.833
−77.299
55.019
1.00
25.97


ATOM
958
SG
CYS
A
667
91.372
−78.176
54.649
1.00
26.74


ATOM
959
N
TYR
A
668
90.131
−79.140
57.810
1.00
25.44


ATOM
960
CA
TYR
A
668
89.875
−80.472
58.356
1.00
25.14


ATOM
961
C
TYR
A
668
89.352
−80.537
59.794
1.00
24.89


ATOM
962
O
TYR
A
668
89.169
−81.626
60.345
1.00
24.75


ATOM
963
CB
TYR
A
668
91.131
−81.331
58.217
1.00
25.46


ATOM
964
CG
TYR
A
668
91.557
−81.513
56.774
1.00
25.84


ATOM
965
CD1
TYR
A
668
92.845
−81.173
56.356
1.00
26.00


ATOM
966
CD2
TYR
A
668
90.660
−82.003
55.821
1.00
26.09


ATOM
967
CE1
TYR
A
668
93.233
−81.309
55.016
1.00
26.30


ATOM
968
CE2
TYR
A
668
91.036
−82.149
54.479
1.00
26.36


ATOM
969
CZ
TYR
A
668
92.323
−81.797
54.084
1.00
26.44


ATOM
970
OH
TYR
A
668
92.695
−81.924
52.763
1.00
26.69


ATOM
971
N
GLY
A
669
89.112
−79.382
60.405
1.00
24.40


ATOM
972
CA
GLY
A
669
88.589
−79.383
61.763
1.00
24.04


ATOM
973
C
GLY
A
669
89.576
−79.747
62.854
1.00
23.62


ATOM
974
O
GLY
A
669
90.789
−79.769
62.628
1.00
23.66


ATOM
975
N
ASP
A
670
89.060
−80.051
64.044
1.00
23.33


ATOM
976
CA
ASP
A
670
89.919
−80.376
65.180
1.00
22.85


ATOM
977
C
ASP
A
670
90.591
−81.741
65.107
1.00
22.68


ATOM
978
O
ASP
A
670
90.050
−82.706
64.561
1.00
22.44


ATOM
979
CB
ASP
A
670
89.145
−80.263
66.501
1.00
22.89


ATOM
980
CG
ASP
A
670
88.184
−81.418
66.718
1.00
22.93


ATOM
981
OD1
ASP
A
670
87.062
−81.363
66.181
1.00
22.83


ATOM
982
OD2
ASP
A
670
88.562
−82.386
67.417
1.00
22.92


ATOM
983
N
LEU
A
671
91.782
−81.803
65.688
1.00
22.48


ATOM
984
CA
LEU
A
671
92.582
−83.015
65.721
1.00
22.38


ATOM
985
C
LEU
A
671
91.951
−84.173
66.489
1.00
22.39


ATOM
986
O
LEU
A
671
92.095
−85.333
66.093
1.00
22.32


ATOM
987
CB
LEU
A
671
93.942
−82.691
66.330
1.00
22.35


ATOM
988
CG
LEU
A
671
94.862
−83.870
66.601
1.00
22.33


ATOM
989
CD1
LEU
A
671
95.220
−84.550
65.288
1.00
22.22


ATOM
990
CD2
LEU
A
671
96.111
−83.358
67.322
1.00
22.20


ATOM
991
N
LEU
A
672
91.259
−83.875
67.585
1.00
22.37


ATOM
992
CA
LEU
A
672
90.648
−84.934
68.382
1.00
22.60


ATOM
993
C
LEU
A
672
89.662
−85.785
67.581
1.00
22.68


ATOM
994
O
LEU
A
672
89.799
−87.003
67.538
1.00
22.56


ATOM
995
CB
LEU
A
672
89.951
−84.355
69.619
1.00
22.59


ATOM
996
CG
LEU
A
672
89.357
−85.399
70.573
1.00
22.64


ATOM
997
CD1
LEU
A
672
90.456
−86.325
71.075
1.00
22.52


ATOM
998
CD2
LEU
A
672
88.678
−84.707
71.746
1.00
22.64


ATOM
999
N
ASN
A
673
88.674
−85.143
66.960
1.00
22.90


ATOM
1000
CA
ASN
A
673
87.673
−85.845
66.144
1.00
23.27


ATOM
1001
C
ASN
A
673
88.387
−86.631
65.043
1.00
23.22


ATOM
1002
O
ASN
A
673
88.028
−87.769
64.731
1.00
23.07


ATOM
1003
CB
ASN
A
673
86.708
−84.834
65.505
1.00
23.73


ATOM
1004
CG
ASN
A
673
85.607
−85.502
64.687
1.00
24.38


ATOM
1005
OD1
ASN
A
673
85.879
−86.279
63.757
1.00
24.96


ATOM
1006
ND2
ASN
A
673
84.353
−85.199
65.024
1.00
24.57


ATOM
1007
N
PHE
A
674
89.408
−86.007
64.461
1.00
23.27


ATOM
1008
CA
PHE
A
674
90.186
−86.635
63.400
1.00
23.31


ATOM
1009
C
PHE
A
674
90.776
−87.953
63.893
1.00
23.38


ATOM
1010
O
PHE
A
674
90.630
−88.991
63.245
1.00
23.32


ATOM
1011
CB
PHE
A
674
91.319
−85.709
62.951
1.00
23.42


ATOM
1012
CG
PHE
A
674
92.158
−86.281
61.843
1.00
23.48


ATOM
1013
CD1
PHE
A
674
91.731
−86.205
60.522
1.00
23.60


ATOM
1014
CD2
PHE
A
674
93.346
−86.941
62.128
1.00
23.46


ATOM
1015
CE1
PHE
A
674
92.481
−86.783
59.491
1.00
23.67


ATOM
1016
CE2
PHE
A
674
94.100
−87.520
61.116
1.00
23.66


ATOM
1017
CZ
PHE
A
674
93.663
−87.441
59.788
1.00
23.59


ATOM
1018
N
LEU
A
675
91.440
−87.903
65.043
1.00
23.43


ATOM
1019
CA
LEU
A
675
92.056
−89.085
65.635
1.00
23.59


ATOM
1020
C
LEU
A
675
91.028
−90.174
65.920
1.00
23.92


ATOM
1021
O
LEU
A
675
91.261
−91.354
65.651
1.00
23.58


ATOM
1022
CB
LEU
A
675
92.763
−88.703
66.938
1.00
23.57


ATOM
1023
CG
LEU
A
675
93.979
−87.775
66.809
1.00
23.45


ATOM
1024
CD1
LEU
A
675
94.417
−87.301
68.191
1.00
23.38


ATOM
1025
CD2
LEU
A
675
95.108
−88.520
66.105
1.00
23.32


ATOM
1026
N
ARG
A
676
89.883
−89.772
66.463
1.00
24.39


ATOM
1027
CA
ARG
A
676
88.843
−90.735
66.797
1.00
25.09


ATOM
1028
C
ARG
A
676
88.274
−91.432
65.568
1.00
25.70


ATOM
1029
O
ARG
A
676
88.018
−92.639
65.598
1.00
25.70


ATOM
1030
CB
ARG
A
676
87.751
−90.054
67.624
1.00
24.72


ATOM
1031
CG
ARG
A
676
88.282
−89.645
68.994
1.00
24.54


ATOM
1032
CD
ARG
A
676
87.254
−88.991
69.902
1.00
24.44


ATOM
1033
NE
ARG
A
676
87.762
−88.941
71.270
1.00
24.27


ATOM
1034
CZ
ARG
A
676
87.134
−88.381
72.297
1.00
24.38


ATOM
1035
NH1
ARG
A
676
85.954
−87.801
72.122
1.00
24.25


ATOM
1036
NH2
ARG
A
676
87.685
−88.412
73.507
1.00
24.23


ATOM
1037
N
ARG
A
677
88.088
−90.689
64.484
1.00
26.52


ATOM
1038
CA
ARG
A
677
87.574
−91.300
63.267
1.00
27.47


ATOM
1039
C
ARG
A
677
88.597
−92.313
62.744
1.00
27.84


ATOM
1040
O
ARG
A
677
88.233
−93.378
62.244
1.00
27.81


ATOM
1041
CB
ARG
A
677
87.275
−90.231
62.214
1.00
27.83


ATOM
1042
CG
ARG
A
677
86.213
−89.233
62.653
1.00
28.52


ATOM
1043
CD
ARG
A
677
85.500
−88.619
61.456
1.00
29.25


ATOM
1044
NE
ARG
A
677
86.441
−88.153
60.445
1.00
29.92


ATOM
1045
CZ
ARG
A
677
87.182
−87.053
60.547
1.00
30.32


ATOM
1046
NH1
ARG
A
677
87.096
−86.278
61.625
1.00
30.62


ATOM
1047
NH2
ARG
A
677
88.028
−86.737
59.573
1.00
30.57


ATOM
1048
N
LYS
A
678
89.878
−91.985
62.876
1.00
28.34


ATOM
1049
CA
LYS
A
678
90.938
−92.883
62.432
1.00
28.96


ATOM
1050
C
LYS
A
678
90.974
−94.161
63.276
1.00
29.41


ATOM
1051
O
LYS
A
678
91.218
−95.252
62.762
1.00
29.35


ATOM
1052
CB
LYS
A
678
92.292
−92.170
62.498
1.00
28.97


ATOM
1053
CG
LYS
A
678
92.532
−91.205
61.345
1.00
28.98


ATOM
1054
CD
LYS
A
678
92.445
−91.943
60.017
1.00
29.14


ATOM
1055
CE
LYS
A
678
92.752
−91.043
58.837
1.00
29.15


ATOM
1056
NZ
LYS
A
678
92.717
−91.820
57.564
1.00
29.15


ATOM
1057
N
ALA
A
679
90.726
−94.019
64.572
1.00
29.95


ATOM
1058
CA
ALA
A
679
90.710
−95.167
65.470
1.00
30.60


ATOM
1059
C
ALA
A
679
89.584
−96.112
65.055
1.00
31.06


ATOM
1060
O
ALA
A
679
89.759
−97.322
65.031
1.00
30.96


ATOM
1061
CB
ALA
A
679
90.499
−94.706
66.910
1.00
30.44


ATOM
1062
N
GLU
A
680
88.432
−95.539
64.727
1.00
31.85


ATOM
1063
CA
GLU
A
680
87.267
−96.313
64.313
1.00
32.66


ATOM
1064
C
GLU
A
680
87.482
−97.062
63.001
1.00
33.10


ATOM
1065
O
GLU
A
680
86.937
−98.150
62.809
1.00
33.18


ATOM
1066
CB
GLU
A
680
86.052
−95.392
64.170
1.00
32.94


ATOM
1067
CG
GLU
A
680
85.546
−94.833
65.484
1.00
33.55


ATOM
1068
CD
GLU
A
680
84.421
−93.821
65.305
1.00
33.97


ATOM
1069
OE1
GLU
A
680
83.864
−93.368
66.336
1.00
34.11


ATOM
1070
OE2
GLU
A
680
84.100
−93.474
64.139
1.00
34.10


ATOM
1071
N
ALA
A
681
88.271
−96.476
62.105
1.00
33.60


ATOM
1072
CA
ALA
A
681
88.545
−97.075
60.798
1.00
34.16


ATOM
1073
C
ALA
A
681
89.727
−98.036
60.841
1.00
34.62


ATOM
1074
O
ALA
A
681
90.085
−98.649
59.831
1.00
34.61


ATOM
1075
CB
ALA
A
681
88.807
−95.980
59.777
1.00
34.09


ATOM
1076
N
MET
A
682
90.329
−98.160
62.015
1.00
35.13


ATOM
1077
CA
MET
A
682
91.467
−99.041
62.208
1.00
35.73


ATOM
1078
C
MET
A
682
91.037
−100.490
62.006
1.00
35.83


ATOM
1079
O
MET
A
682
89.963
−100.902
62.449
1.00
35.86


ATOM
1080
CB
MET
A
682
92.023
−98.855
63.621
1.00
36.31


ATOM
1081
CG
MET
A
682
93.404
−99.429
63.839
1.00
37.06


ATOM
1082
SD
MET
A
682
94.615
−98.662
62.747
1.00
38.11


ATOM
1083
CE
MET
A
682
94.897
−97.104
63.607
1.00
37.91


ATOM
1084
N
LEU
A
683
91.876
−101.255
61.322
1.00
35.95


ATOM
1085
CA
LEU
A
683
91.595
−102.660
61.073
1.00
36.17


ATOM
1086
C
LEU
A
683
90.290
−102.813
60.288
1.00
36.32


ATOM
1087
O
LEU
A
683
89.346
−103.474
60.729
1.00
36.35


ATOM
1088
CB
LEU
A
683
91.512
−103.405
62.409
1.00
36.03


ATOM
1089
CG
LEU
A
683
91.955
−104.864
62.381
1.00
36.11


ATOM
1090
CD1
LEU
A
683
91.699
−105.515
63.733
1.00
36.05


ATOM
1091
CD2
LEU
A
683
91.198
−105.575
61.290
1.00
36.08


ATOM
1092
N
GLY
A
684
90.246
−102.181
59.123
1.00
36.53


ATOM
1093
CA
GLY
A
684
89.069
−102.247
58.277
1.00
36.70


ATOM
1094
C
GLY
A
684
89.413
−102.942
56.978
1.00
36.76


ATOM
1095
OT1
GLY
A
684
88.572
−103.696
56.455
1.00
36.87


ATOM
1096
OT2
GLY
A
684
90.531
−102.719
56.476
1.00
36.86


ATOM
1097
N
ALA
A
746
88.595
−102.096
54.093
1.00
42.36


ATOM
1098
CA
ALA
A
746
89.480
−101.002
53.609
1.00
42.33


ATOM
1099
C
ALA
A
746
89.659
−99.952
54.694
1.00
42.32


ATOM
1100
O
ALA
A
746
88.693
−99.526
55.328
1.00
42.43


ATOM
1101
CB
ALA
A
746
88.891
−100.360
52.361
1.00
42.39


ATOM
1102
N
GLY
A
747
90.903
−99.536
54.898
1.00
42.17


ATOM
1103
CA
GLY
A
747
91.197
−98.535
55.903
1.00
41.91


ATOM
1104
C
GLY
A
747
92.560
−97.930
55.651
1.00
41.70


ATOM
1105
O
GLY
A
747
93.482
−98.621
55.210
1.00
41.75


ATOM
1106
N
ARG
A
748
92.686
−96.635
55.925
1.00
41.39


ATOM
1107
CA
ARG
A
748
93.943
−95.919
55.731
1.00
41.02


ATOM
1108
C
ARG
A
748
94.390
−95.354
57.081
1.00
40.55


ATOM
1109
O
ARG
A
748
94.214
−94.168
57.364
1.00
40.56


ATOM
1110
CB
ARG
A
748
93.734
−94.805
54.702
1.00
41.29


ATOM
1111
CG
ARG
A
748
93.396
−95.342
53.311
1.00
41.67


ATOM
1112
CD
ARG
A
748
92.366
−94.484
52.572
1.00
41.96


ATOM
1113
NE
ARG
A
748
91.029
−94.589
53.161
1.00
42.31


ATOM
1114
CZ
ARG
A
748
89.929
−94.063
52.627
1.00
42.44


ATOM
1115
NH1
ARG
A
748
89.995
−93.389
51.483
1.00
42.56


ATOM
1116
NH2
ARG
A
748
88.759
−94.210
53.234
1.00
42.52


ATOM
1117
N
PRO
A
749
94.986
−96.210
57.929
1.00
40.03


ATOM
1118
CA
PRO
A
749
95.474
−95.862
59.269
1.00
39.51


ATOM
1119
C
PRO
A
749
96.614
−94.856
59.357
1.00
38.97


ATOM
1120
O
PRO
A
749
97.361
−94.648
58.399
1.00
38.93


ATOM
1121
CB
PRO
A
749
95.871
−97.218
59.849
1.00
39.70


ATOM
1122
CG
PRO
A
749
96.371
−97.945
58.647
1.00
39.84


ATOM
1123
CD
PRO
A
749
95.313
−97.614
57.611
1.00
39.97


ATOM
1124
N
LEU
A
750
96.736
−94.237
60.528
1.00
38.23


ATOM
1125
CA
LEU
A
750
97.796
−93.271
60.783
1.00
37.42


ATOM
1126
C
LEU
A
750
99.033
−94.032
61.256
1.00
36.85


ATOM
1127
O
LEU
A
750
98.984
−94.740
62.264
1.00
36.83


ATOM
1128
CB
LEU
A
750
97.362
−92.273
61.863
1.00
37.41


ATOM
1129
CG
LEU
A
750
96.234
−91.289
61.532
1.00
37.43


ATOM
1130
CD1
LEU
A
750
95.869
−90.497
62.778
1.00
37.35


ATOM
1131
CD2
LEU
A
750
96.674
−90.352
60.415
1.00
37.44


ATOM
1132
N
GLU
A
751
100.138
−93.896
60.529
1.00
36.08


ATOM
1133
CA
GLU
A
751
101.371
−94.577
60.905
1.00
35.34


ATOM
1134
C
GLU
A
751
102.196
−93.670
61.809
1.00
34.78


ATOM
1135
O
GLU
A
751
101.892
−92.486
61.942
1.00
34.71


ATOM
1136
CB
GLU
A
751
102.181
−94.950
59.661
1.00
35.39


ATOM
1137
CG
GLU
A
751
101.476
−95.904
58.695
1.00
35.35


ATOM
1138
CD
GLU
A
751
101.063
−97.220
59.344
1.00
35.41


ATOM
1139
OE1
GLU
A
751
101.698
−97.629
60.341
1.00
35.34


ATOM
1140
OE2
GLU
A
751
100.111
−97.856
58.841
1.00
35.37


ATOM
1141
N
LEU
A
752
103.235
−94.226
62.429
1.00
34.02


ATOM
1142
CA
LEU
A
752
104.086
−93.452
63.329
1.00
33.37


ATOM
1143
C
LEU
A
752
104.466
−92.103
62.735
1.00
32.85


ATOM
1144
O
LEU
A
752
104.450
−91.086
63.426
1.00
32.87


ATOM
1145
CB
LEU
A
752
105.363
−94.228
63.674
1.00
33.25


ATOM
1146
CG
LEU
A
752
106.380
−93.439
64.509
1.00
33.20


ATOM
1147
CD1
LEU
A
752
105.742
−93.019
65.821
1.00
33.12


ATOM
1148
CD2
LEU
A
752
107.616
−94.289
64.779
1.00
33.15


ATOM
1149
N
ARG
A
753
104.818
−92.105
61.453
1.00
32.25


ATOM
1150
CA
ARG
A
753
105.206
−90.887
60.749
1.00
31.50


ATOM
1151
C
ARG
A
753
104.147
−89.792
60.892
1.00
30.74


ATOM
1152
O
ARG
A
753
104.465
−88.641
61.194
1.00
30.57


ATOM
1153
CB
ARG
A
753
105.427
−91.203
59.264
1.00
32.00


ATOM
1154
CG
ARG
A
753
105.528
−89.983
58.359
1.00
32.68


ATOM
1155
CD
ARG
A
753
105.459
−90.388
56.884
1.00
33.29


ATOM
1156
NE
ARG
A
753
105.351
−89.229
55.995
1.00
33.77


ATOM
1157
CZ
ARG
A
753
106.348
−88.389
55.723
1.00
34.04


ATOM
1158
NH1
ARG
A
753
106.144
−87.363
54.904
1.00
34.18


ATOM
1159
NH2
ARG
A
753
107.551
−88.577
56.262
1.00
34.17


ATOM
1160
N
ASP
A
754
102.890
−90.159
60.676
1.00
29.72


ATOM
1161
CA
ASP
A
754
101.785
−89.209
60.761
1.00
28.83


ATOM
1162
C
ASP
A
754
101.615
−88.630
62.166
1.00
28.10


ATOM
1163
O
ASP
A
754
101.440
−87.423
62.333
1.00
27.92


ATOM
1164
CB
ASP
A
754
100.484
−89.887
60.326
1.00
28.94


ATOM
1165
CG
ASP
A
754
100.585
−90.503
58.943
1.00
29.03


ATOM
1166
OD1
ASP
A
754
100.822
−89.753
57.975
1.00
29.08


ATOM
1167
OD2
ASP
A
754
100.430
−91.735
58.828
1.00
28.98


ATOM
1168
N
LEU
A
755
101.667
−89.499
63.168
1.00
27.28


ATOM
1169
CA
LEU
A
755
101.507
−89.083
64.553
1.00
26.58


ATOM
1170
C
LEU
A
755
102.668
−88.188
64.978
1.00
26.24


ATOM
1171
O
LEU
A
755
102.469
−87.216
65.703
1.00
25.98


ATOM
1172
CB
LEU
A
755
101.402
−90.311
65.454
1.00
26.42


ATOM
1173
CG
LEU
A
755
100.218
−91.220
65.080
1.00
26.21


ATOM
1174
CD1
LEU
A
755
100.196
−92.441
65.972
1.00
26.14


ATOM
1175
CD2
LEU
A
755
98.906
−90.446
65.205
1.00
26.14


ATOM
1176
N
LEU
A
756
103.874
−88.518
64.514
1.00
25.81


ATOM
1177
CA
LEU
A
756
105.058
−87.721
64.822
1.00
25.49


ATOM
1178
C
LEU
A
756
104.914
−86.318
64.245
1.00
25.28


ATOM
1179
O
LEU
A
756
105.310
−85.341
64.876
1.00
25.25


ATOM
1180
CB
LEU
A
756
106.319
−88.379
64.251
1.00
25.37


ATOM
1181
CG
LEU
A
756
106.804
−89.652
64.961
1.00
25.29


ATOM
1182
CD1
LEU
A
756
108.041
−90.196
64.260
1.00
25.29


ATOM
1183
CD2
LEU
A
756
107.119
−89.340
66.416
1.00
25.25


ATOM
1184
N
HIS
A
757
104.360
−86.221
63.038
1.00
25.08


ATOM
1185
CA
HIS
A
757
104.163
−84.919
62.400
1.00
24.86


ATOM
1186
C
HIS
A
757
103.213
−84.051
63.220
1.00
24.35


ATOM
1187
O
HIS
A
757
103.489
−82.876
63.454
1.00
24.21


ATOM
1188
CB
HIS
A
757
103.587
−85.060
60.984
1.00
25.39


ATOM
1189
CG
HIS
A
757
104.554
−85.605
59.982
1.00
26.00


ATOM
1190
ND1
HIS
A
757
105.913
−85.379
60.059
1.00
26.34


ATOM
1191
CD2
HIS
A
757
104.356
−86.325
58.850
1.00
26.28


ATOM
1192
CE1
HIS
A
757
106.510
−85.937
59.020
1.00
26.44


ATOM
1193
NE2
HIS
A
757
105.587
−86.517
58.270
1.00
26.38


ATOM
1194
N
PHE
A
758
102.086
−84.621
63.639
1.00
23.77


ATOM
1195
CA
PHE
A
758
101.129
−83.858
64.434
1.00
23.21


ATOM
1196
C
PHE
A
758
101.812
−83.363
65.704
1.00
22.83


ATOM
1197
O
PHE
A
758
101.682
−82.203
66.075
1.00
22.65


ATOM
1198
CB
PHE
A
758
99.917
−84.713
64.824
1.00
23.16


ATOM
1199
CG
PHE
A
758
99.043
−85.116
63.670
1.00
23.16


ATOM
1200
CD1
PHE
A
758
98.776
−84.227
62.628
1.00
23.07


ATOM
1201
CD2
PHE
A
758
98.450
−86.376
63.646
1.00
23.18


ATOM
1202
CE1
PHE
A
758
97.930
−84.588
61.577
1.00
23.15


ATOM
1203
CE2
PHE
A
758
97.600
−86.751
62.602
1.00
23.18


ATOM
1204
CZ
PHE
A
758
97.340
−85.855
61.565
1.00
23.13


ATOM
1205
N
SER
A
759
102.547
−84.261
66.353
1.00
22.50


ATOM
1206
CA
SER
A
759
103.256
−83.956
67.590
1.00
22.33


ATOM
1207
C
SER
A
759
104.296
−82.853
67.402
1.00
22.28


ATOM
1208
O
SER
A
759
104.407
−81.947
68.233
1.00
22.19


ATOM
1209
CB
SER
A
759
103.951
−85.215
68.116
1.00
22.28


ATOM
1210
OG
SER
A
759
103.039
−86.292
68.221
1.00
22.03


ATOM
1211
N
SER
A
760
105.059
−82.933
66.315
1.00
22.18


ATOM
1212
CA
SER
A
760
106.084
−81.934
66.038
1.00
22.13


ATOM
1213
C
SER
A
760
105.454
−80.593
65.700
1.00
21.99


ATOM
1214
O
SER
A
760
105.908
−79.544
66.172
1.00
21.86


ATOM
1215
CB
SER
A
760
106.982
−82.384
64.882
1.00
22.34


ATOM
1216
OG
SER
A
760
107.856
−83.417
65.305
1.00
22.79


ATOM
1217
N
GLN
A
761
104.403
−80.630
64.890
1.00
21.79


ATOM
1218
CA
GLN
A
761
103.721
−79.408
64.502
1.00
21.62


ATOM
1219
C
GLN
A
761
103.163
−78.658
65.707
1.00
21.42


ATOM
1220
O
GLN
A
761
103.353
−77.441
65.829
1.00
21.42


ATOM
1221
CB
GLN
A
761
102.619
−79.731
63.498
1.00
21.99


ATOM
1222
CG
GLN
A
761
103.130
−79.810
62.064
1.00
22.39


ATOM
1223
CD
GLN
A
761
102.384
−80.830
61.222
1.00
22.67


ATOM
1224
OE1
GLN
A
761
101.190
−81.073
61.419
1.00
22.81


ATOM
1225
NE2
GLN
A
761
103.085
−81.418
60.261
1.00
22.94


ATOM
1226
N
VAL
A
762
102.487
−79.366
66.606
1.00
21.02


ATOM
1227
CA
VAL
A
762
101.944
−78.698
67.784
1.00
20.78


ATOM
1228
C
VAL
A
762
103.070
−78.188
68.696
1.00
20.65


ATOM
1229
O
VAL
A
762
102.983
−77.086
69.232
1.00
20.47


ATOM
1230
CB
VAL
A
762
100.975
−79.629
68.561
1.00
20.80


ATOM
1231
CG1
VAL
A
762
100.515
−78.965
69.857
1.00
20.48


ATOM
1232
CG2
VAL
A
762
99.763
−79.940
67.686
1.00
20.54


ATOM
1233
N
ALA
A
763
104.133
−78.975
68.851
1.00
20.65


ATOM
1234
CA
ALA
A
763
105.254
−78.567
69.691
1.00
20.63


ATOM
1235
C
ALA
A
763
105.881
−77.281
69.154
1.00
20.67


ATOM
1236
O
ALA
A
763
106.363
−76.452
69.918
1.00
20.60


ATOM
1237
CB
ALA
A
763
106.305
−79.672
69.745
1.00
20.64


ATOM
1238
N
GLN
A
764
105.880
−77.136
67.833
1.00
20.67


ATOM
1239
CA
GLN
A
764
106.439
−75.961
67.185
1.00
20.73


ATOM
1240
C
GLN
A
764
105.542
−74.765
67.470
1.00
20.46


ATOM
1241
O
GLN
A
764
106.024
−73.658
67.717
1.00
20.40


ATOM
1242
CB
GLN
A
764
106.558
−76.197
65.669
1.00
21.21


ATOM
1243
CG
GLN
A
764
107.552
−77.295
65.282
1.00
21.99


ATOM
1244
CD
GLN
A
764
107.602
−77.565
63.771
1.00
22.57


ATOM
1245
OE1
GLN
A
764
108.390
−78.395
63.304
1.00
22.87


ATOM
1246
NE2
GLN
A
764
106.758
−76.867
63.006
1.00
22.80


ATOM
1247
N
GLY
A
765
104.232
−74.992
67.439
1.00
20.17


ATOM
1248
CA
GLY
A
765
103.296
−73.916
67.716
1.00
19.80


ATOM
1249
C
GLY
A
765
103.424
−73.453
69.160
1.00
19.63


ATOM
1250
O
GLY
A
765
103.404
−72.254
69.443
1.00
19.51


ATOM
1251
N
MET
A
766
103.575
−74.405
70.076
1.00
19.39


ATOM
1252
CA
MET
A
766
103.720
−74.084
71.498
1.00
19.19


ATOM
1253
C
MET
A
766
105.036
−73.348
71.759
1.00
19.27


ATOM
1254
O
MET
A
766
105.081
−72.409
72.563
1.00
19.31


ATOM
1255
CB
MET
A
766
103.678
−75.357
72.352
1.00
19.00


ATOM
1256
CG
MET
A
766
102.309
−76.022
72.435
1.00
18.69


ATOM
1257
SD
MET
A
766
101.007
−74.837
72.861
1.00
18.49


ATOM
1258
CE
MET
A
766
101.445
−74.404
74.562
1.00
18.39


ATOM
1259
N
ALA
A
767
106.105
−73.780
71.090
1.00
19.26


ATOM
1260
CA
ALA
A
767
107.405
−73.131
71.247
1.00
19.27


ATOM
1261
C
ALA
A
767
107.282
−71.658
70.864
1.00
19.39


ATOM
1262
O
ALA
A
767
107.935
−70.796
71.464
1.00
19.41


ATOM
1263
CB
ALA
A
767
108.452
−73.814
70.375
1.00
19.29


ATOM
1264
N
PHE
A
768
106.458
−71.368
69.857
1.00
19.34


ATOM
1265
CA
PHE
A
768
106.249
−69.987
69.423
1.00
19.41


ATOM
1266
C
PHE
A
768
105.504
−69.213
70.504
1.00
19.44


ATOM
1267
O
PHE
A
768
105.840
−68.058
70.807
1.00
19.35


ATOM
1268
CB
PHE
A
768
105.438
−69.938
68.128
1.00
19.37


ATOM
1269
CG
PHE
A
768
105.128
−68.546
67.661
1.00
19.44


ATOM
1270
CD1
PHE
A
768
106.130
−67.732
67.133
1.00
19.32


ATOM
1271
CD2
PHE
A
768
103.836
−68.034
67.769
1.00
19.38


ATOM
1272
CE1
PHE
A
768
105.846
−66.436
66.723
1.00
19.39


ATOM
1273
CE2
PHE
A
768
103.546
−66.735
67.361
1.00
19.30


ATOM
1274
CZ
PHE
A
768
104.551
−65.937
66.838
1.00
19.47


ATOM
1275
N
LEU
A
769
104.478
−69.838
71.073
1.00
19.35


ATOM
1276
CA
LEU
A
769
103.709
−69.189
72.129
1.00
19.46


ATOM
1277
C
LEU
A
769
104.621
−68.910
73.308
1.00
19.56


ATOM
1278
O
LEU
A
769
104.569
−67.829
73.909
1.00
19.53


ATOM
1279
CB
LEU
A
769
102.535
−70.073
72.570
1.00
19.40


ATOM
1280
CG
LEU
A
769
101.405
−70.233
71.551
1.00
19.33


ATOM
1281
CD1
LEU
A
769
100.254
−70.985
72.204
1.00
19.39


ATOM
1282
CD2
LEU
A
769
100.926
−68.862
71.075
1.00
19.35


ATOM
1283
N
ALA
A
770
105.470
−69.886
73.626
1.00
19.68


ATOM
1284
CA
ALA
A
770
106.420
−69.753
74.723
1.00
19.84


ATOM
1285
C
ALA
A
770
107.416
−68.628
74.442
1.00
20.01


ATOM
1286
O
ALA
A
770
107.835
−67.932
75.359
1.00
20.07


ATOM
1287
CB
ALA
A
770
107.168
−71.074
74.936
1.00
19.65


ATOM
1288
N
SER
A
771
107.785
−68.445
73.176
1.00
20.26


ATOM
1289
CA
SER
A
771
108.735
−67.400
72.813
1.00
20.48


ATOM
1290
C
SER
A
771
108.124
−66.010
72.998
1.00
20.72


ATOM
1291
O
SER
A
771
108.835
−65.006
73.005
1.00
20.73


ATOM
1292
CB
SER
A
771
109.226
−67.586
71.366
1.00
20.51


ATOM
1293
OG
SER
A
771
108.237
−67.231
70.422
1.00
20.38


ATOM
1294
N
LYS
A
772
106.806
−65.948
73.162
1.00
20.92


ATOM
1295
CA
LYS
A
772
106.144
−64.669
73.382
1.00
21.21


ATOM
1296
C
LYS
A
772
105.717
−64.543
74.844
1.00
21.13


ATOM
1297
O
LYS
A
772
104.961
−63.638
75.209
1.00
21.19


ATOM
1298
CB
LYS
A
772
104.929
−64.533
72.464
1.00
21.62


ATOM
1299
CG
LYS
A
772
105.302
−64.497
70.993
1.00
22.18


ATOM
1300
CD
LYS
A
772
106.385
−63.446
70.761
1.00
22.61


ATOM
1301
CE
LYS
A
772
106.805
−63.373
69.303
1.00
22.93


ATOM
1302
NZ
LYS
A
772
105.700
−62.853
68.468
1.00
22.97


ATOM
1303
N
ASN
A
773
106.224
−65.452
75.674
1.00
21.06


ATOM
1304
CA
ASN
A
773
105.905
−65.493
77.094
1.00
21.07


ATOM
1305
C
ASN
A
773
104.407
−65.630
77.293
1.00
21.06


ATOM
1306
O
ASN
A
773
103.831
−65.052
78.209
1.00
20.96


ATOM
1307
CB
ASN
A
773
106.407
−64.237
77.815
1.00
21.33


ATOM
1308
CG
ASN
A
773
107.895
−64.249
78.018
1.00
21.44


ATOM
1309
OD1
ASN
A
773
108.508
−65.316
78.136
1.00
21.65


ATOM
1310
ND2
ASN
A
773
108.495
−63.063
78.086
1.00
21.56


ATOM
1311
N
CYS
A
774
103.784
−66.416
76.425
1.00
21.18


ATOM
1312
CA
CYS
A
774
102.345
−66.636
76.497
1.00
21.32


ATOM
1313
C
CYS
A
774
102.003
−68.011
77.051
1.00
21.18


ATOM
1314
O
CYS
A
774
102.476
−69.025
76.541
1.00
21.28


ATOM
1315
CB
CYS
A
774
101.720
−66.482
75.102
1.00
21.51


ATOM
1316
SG
CYS
A
774
99.925
−66.774
75.059
1.00
22.30


ATOM
1317
N
ILE
A
775
101.201
−68.038
78.113
1.00
20.97


ATOM
1318
CA
ILE
A
775
100.753
−69.297
78.697
1.00
20.77


ATOM
1319
C
ILE
A
775
99.348
−69.496
78.114
1.00
20.32


ATOM
1320
O
ILE
A
775
98.530
−68.572
78.120
1.00
20.46


ATOM
1321
CB
ILE
A
775
100.686
−69.229
80.247
1.00
21.01


ATOM
1322
CG1
ILE
A
775
99.892
−67.996
80.685
1.00
21.19


ATOM
1323
CG2
ILE
A
775
102.091
−69.202
80.832
1.00
21.09


ATOM
1324
CD1
ILE
A
775
99.782
−67.847
82.192
1.00
21.58


ATOM
1325
N
HIS
A
776
99.099
−70.692
77.594
1.00
19.70


ATOM
1326
CA
HIS
A
776
97.842
−71.055
76.948
1.00
19.19


ATOM
1327
C
HIS
A
776
96.757
−71.483
77.943
1.00
18.74


ATOM
1328
O
HIS
A
776
95.642
−70.967
77.932
1.00
18.67


ATOM
1329
CB
HIS
A
776
98.149
−72.180
75.956
1.00
19.07


ATOM
1330
CG
HIS
A
776
97.002
−72.575
75.088
1.00
18.88


ATOM
1331
ND1
HIS
A
776
95.848
−73.142
75.587
1.00
18.75


ATOM
1332
CD2
HIS
A
776
96.861
−72.554
73.741
1.00
18.82


ATOM
1333
CE1
HIS
A
776
95.049
−73.457
74.585
1.00
18.84


ATOM
1334
NE2
HIS
A
776
95.639
−73.112
73.454
1.00
18.70


ATOM
1335
N
ARG
A
777
97.105
−72.452
78.778
1.00
18.38


ATOM
1336
CA
ARG
A
777
96.242
−72.990
79.822
1.00
18.01


ATOM
1337
C
ARG
A
777
95.101
−73.913
79.412
1.00
17.59


ATOM
1338
O
ARG
A
777
94.335
−74.354
80.264
1.00
17.80


ATOM
1339
CB
ARG
A
777
95.738
−71.861
80.724
1.00
18.26


ATOM
1340
CG
ARG
A
777
96.908
−71.143
81.422
1.00
18.67


ATOM
1341
CD
ARG
A
777
96.527
−70.527
82.756
1.00
19.00


ATOM
1342
NE
ARG
A
777
95.817
−69.266
82.589
1.00
19.53


ATOM
1343
CZ
ARG
A
777
95.352
−68.524
83.593
1.00
19.85


ATOM
1344
NH1
ARG
A
777
95.515
−68.907
84.859
1.00
19.85


ATOM
1345
NH2
ARG
A
777
94.725
−67.391
83.328
1.00
20.06


ATOM
1346
N
ASP
A
778
94.963
−74.190
78.119
1.00
16.97


ATOM
1347
CA
ASP
A
778
93.957
−75.162
77.692
1.00
16.55


ATOM
1348
C
ASP
A
778
94.510
−75.952
76.516
1.00
16.38


ATOM
1349
O
ASP
A
778
93.849
−76.130
75.506
1.00
16.52


ATOM
1350
CB
ASP
A
778
92.618
−74.512
77.322
1.00
16.13


ATOM
1351
CG
ASP
A
778
91.493
−75.540
77.225
1.00
15.88


ATOM
1352
OD1
ASP
A
778
91.743
−76.727
77.529
1.00
15.51


ATOM
1353
OD2
ASP
A
778
90.364
−75.169
76.850
1.00
15.68


ATOM
1354
N
VAL
A
779
95.749
−76.414
76.660
1.00
16.12


ATOM
1355
CA
VAL
A
779
96.397
−77.193
75.623
1.00
16.00


ATOM
1356
C
VAL
A
779
95.792
−78.586
75.661
1.00
15.81


ATOM
1357
O
VAL
A
779
95.834
−79.250
76.687
1.00
15.72


ATOM
1358
CB
VAL
A
779
97.922
−77.310
75.871
1.00
16.07


ATOM
1359
CG1
VAL
A
779
98.544
−78.238
74.839
1.00
16.03


ATOM
1360
CG2
VAL
A
779
98.568
−75.921
75.833
1.00
15.76


ATOM
1361
N
ALA
A
780
95.243
−79.016
74.534
1.00
15.64


ATOM
1362
CA
ALA
A
780
94.604
−80.324
74.428
1.00
15.73


ATOM
1363
C
ALA
A
780
94.282
−80.569
72.957
1.00
15.55


ATOM
1364
O
ALA
A
780
94.194
−79.624
72.180
1.00
15.59


ATOM
1365
CB
ALA
A
780
93.312
−80.350
75.277
1.00
15.59


ATOM
1366
N
ALA
A
781
94.092
−81.833
72.581
1.00
15.63


ATOM
1367
CA
ALA
A
781
93.805
−82.186
71.187
1.00
15.62


ATOM
1368
C
ALA
A
781
92.598
−81.456
70.601
1.00
15.71


ATOM
1369
O
ALA
A
781
92.581
−81.118
69.414
1.00
15.62


ATOM
1370
CB
ALA
A
781
93.604
−83.701
71.065
1.00
15.74


ATOM
1371
N
ARG
A
782
91.585
−81.229
71.434
1.00
15.78


ATOM
1372
CA
ARG
A
782
90.368
−80.555
71.005
1.00
15.99


ATOM
1373
C
ARG
A
782
90.608
−79.106
70.573
1.00
16.25


ATOM
1374
O
ARG
A
782
89.743
−78.489
69.938
1.00
16.22


ATOM
1375
CB
ARG
A
782
89.325
−80.580
72.134
1.00
15.86


ATOM
1376
CG
ARG
A
782
89.776
−79.904
73.420
1.00
15.77


ATOM
1377
CD
ARG
A
782
88.660
−79.814
74.479
1.00
15.74


ATOM
1378
NE
ARG
A
782
89.198
−79.262
75.728
1.00
15.69


ATOM
1379
CZ
ARG
A
782
89.844
−79.981
76.643
1.00
15.79


ATOM
1380
NH1
ARG
A
782
90.015
−81.289
76.469
1.00
15.61


ATOM
1381
NH2
ARG
A
782
90.382
−79.382
77.705
1.00
15.71


ATOM
1382
N
ASN
A
783
91.763
−78.552
70.924
1.00
16.44


ATOM
1383
CA
ASN
A
783
92.042
−77.170
70.546
1.00
16.82


ATOM
1384
C
ASN
A
783
93.054
−77.054
69.426
1.00
16.96


ATOM
1385
O
ASN
A
783
93.526
−75.957
69.122
1.00
16.81


ATOM
1386
CB
ASN
A
783
92.499
−76.354
71.755
1.00
16.87


ATOM
1387
CG
ASN
A
783
91.331
−75.849
72.586
1.00
17.03


ATOM
1388
OD1
ASN
A
783
90.336
−75.354
72.039
1.00
17.26


ATOM
1389
ND2
ASN
A
783
91.452
−75.948
73.912
1.00
16.77


ATOM
1390
N
VAL
A
784
93.381
−78.190
68.819
1.00
17.17


ATOM
1391
CA
VAL
A
784
94.313
−78.205
67.701
1.00
17.56


ATOM
1392
C
VAL
A
784
93.480
−78.425
66.441
1.00
18.01


ATOM
1393
O
VAL
A
784
92.622
−79.315
66.396
1.00
17.85


ATOM
1394
CB
VAL
A
784
95.360
−79.356
67.805
1.00
17.46


ATOM
1395
CG1
VAL
A
784
96.282
−79.320
66.592
1.00
17.43


ATOM
1396
CG2
VAL
A
784
96.178
−79.231
69.080
1.00
17.31


ATOM
1397
N
LEU
A
785
93.709
−77.595
65.432
1.00
18.59


ATOM
1398
CA
LEU
A
785
92.989
−77.734
64.173
1.00
19.34


ATOM
1399
C
LEU
A
785
93.929
−78.248
63.089
1.00
19.84


ATOM
1400
O
LEU
A
785
95.145
−78.078
63.179
1.00
19.93


ATOM
1401
CB
LEU
A
785
92.390
−76.397
63.735
1.00
19.34


ATOM
1402
CG
LEU
A
785
91.372
−75.717
64.654
1.00
19.64


ATOM
1403
CD1
LEU
A
785
90.839
−74.476
63.974
1.00
19.53


ATOM
1404
CD2
LEU
A
785
90.223
−76.671
64.977
1.00
19.81


ATOM
1405
N
LEU
A
786
93.352
−78.884
62.071
1.00
20.53


ATOM
1406
CA
LEU
A
786
94.107
−79.431
60.949
1.00
21.15


ATOM
1407
C
LEU
A
786
93.736
−78.647
59.696
1.00
21.56


ATOM
1408
O
LEU
A
786
92.562
−78.529
59.351
1.00
21.51


ATOM
1409
CB
LEU
A
786
93.770
−80.915
60.755
1.00
21.14


ATOM
1410
CG
LEU
A
786
94.194
−81.852
61.887
1.00
21.29


ATOM
1411
CD1
LEU
A
786
93.671
−83.256
61.622
1.00
21.21


ATOM
1412
CD2
LEU
A
786
95.710
−81.852
62.005
1.00
21.17


ATOM
1413
N
THR
A
787
94.743
−78.103
59.023
1.00
22.17


ATOM
1414
CA
THR
A
787
94.507
−77.313
57.821
1.00
22.84


ATOM
1415
C
THR
A
787
94.984
−78.055
56.569
1.00
23.21


ATOM
1416
O
THR
A
787
95.142
−79.273
56.587
1.00
23.18


ATOM
1417
CB
THR
A
787
95.228
−75.950
57.923
1.00
22.80


ATOM
1418
OG1
THR
A
787
94.761
−75.089
56.880
1.00
23.25


ATOM
1419
CG2
THR
A
787
96.736
−76.125
57.799
1.00
22.85


ATOM
1420
N
ASN
A
788
95.213
−77.314
55.486
1.00
23.77


ATOM
1421
CA
ASN
A
788
95.685
−77.910
54.235
1.00
24.29


ATOM
1422
C
ASN
A
788
96.904
−78.804
54.467
1.00
24.28


ATOM
1423
O
ASN
A
788
97.840
−78.424
55.170
1.00
24.37


ATOM
1424
CB
ASN
A
788
96.047
−76.812
53.234
1.00
24.80


ATOM
1425
CG
ASN
A
788
94.859
−75.956
52.862
1.00
25.30


ATOM
1426
OD1
ASN
A
788
93.900
−76.434
52.251
1.00
25.88


ATOM
1427
ND2
ASN
A
788
94.909
−74.682
53.229
1.00
25.69


ATOM
1428
N
GLY
A
789
96.886
−79.990
53.865
1.00
24.31


ATOM
1429
CA
GLY
A
789
97.987
−80.924
54.018
1.00
24.30


ATOM
1430
C
GLY
A
789
97.956
−81.575
55.388
1.00
24.32


ATOM
1431
O
GLY
A
789
98.909
−82.236
55.795
1.00
24.41


ATOM
1432
N
HIS
A
790
96.832
−81.403
56.078
1.00
24.25


ATOM
1433
CA
HIS
A
790
96.624
−81.918
57.424
1.00
24.08


ATOM
1434
C
HIS
A
790
97.721
−81.432
58.368
1.00
23.82


ATOM
1435
O
HIS
A
790
98.221
−82.176
59.217
1.00
23.82


ATOM
1436
CB
HIS
A
790
96.535
−83.452
57.434
1.00
24.35


ATOM
1437
CG
HIS
A
790
95.231
−83.985
56.916
1.00
24.71


ATOM
1438
ND1
HIS
A
790
94.933
−84.056
55.570
1.00
24.82


ATOM
1439
CD2
HIS
A
790
94.133
−84.443
57.567
1.00
24.89


ATOM
1440
CE1
HIS
A
790
93.709
−84.536
55.416
1.00
24.86


ATOM
1441
NE2
HIS
A
790
93.201
−84.777
56.611
1.00
24.85


ATOM
1442
N
VAL
A
791
98.099
−80.171
58.201
1.00
23.41


ATOM
1443
CA
VAL
A
791
99.114
−79.559
59.047
1.00
23.14


ATOM
1444
C
VAL
A
791
98.430
−79.119
60.340
1.00
22.73


ATOM
1445
O
VAL
A
791
97.424
−78.420
60.302
1.00
22.65


ATOM
1446
CB
VAL
A
791
99.729
−78.315
58.374
1.00
23.28


ATOM
1447
CG1
VAL
A
791
100.668
−77.611
59.348
1.00
23.39


ATOM
1448
CG2
VAL
A
791
100.477
−78.723
57.112
1.00
23.45


ATOM
1449
N
ALA
A
792
98.989
−79.523
61.474
1.00
22.39


ATOM
1450
CA
ALA
A
792
98.422
−79.191
62.773
1.00
22.01


ATOM
1451
C
ALA
A
792
98.757
−77.780
63.250
1.00
21.71


ATOM
1452
O
ALA
A
792
99.890
−77.305
63.101
1.00
21.62


ATOM
1453
CB
ALA
A
792
98.885
−80.210
63.809
1.00
22.06


ATOM
1454
N
LYS
A
793
97.753
−77.129
63.830
1.00
21.15


ATOM
1455
CA
LYS
A
793
97.879
−75.781
64.373
1.00
20.68


ATOM
1456
C
LYS
A
793
97.227
−75.710
65.763
1.00
20.31


ATOM
1457
O
LYS
A
793
96.073
−76.108
65.936
1.00
20.14


ATOM
1458
CB
LYS
A
793
97.187
−74.770
63.451
1.00
20.80


ATOM
1459
CG
LYS
A
793
97.919
−74.477
62.143
1.00
20.74


ATOM
1460
CD
LYS
A
793
97.058
−73.580
61.240
1.00
20.74


ATOM
1461
CE
LYS
A
793
97.871
−72.988
60.088
1.00
20.72


ATOM
1462
NZ
LYS
A
793
98.714
−71.841
60.544
1.00
20.67


ATOM
1463
N
ILE
A
794
97.962
−75.206
66.747
1.00
19.86


ATOM
1464
CA
ILE
A
794
97.409
−75.070
68.085
1.00
19.48


ATOM
1465
C
ILE
A
794
96.645
−73.748
68.164
1.00
19.44


ATOM
1466
O
ILE
A
794
97.091
−72.720
67.649
1.00
19.47


ATOM
1467
CB
ILE
A
794
98.511
−75.101
69.183
1.00
19.20


ATOM
1468
CG1
ILE
A
794
97.886
−74.955
70.580
1.00
19.08


ATOM
1469
CG2
ILE
A
794
99.516
−73.970
68.961
1.00
19.16


ATOM
1470
CD1
ILE
A
794
96.852
−76.011
70.929
1.00
18.76


ATOM
1471
N
GLY
A
795
95.470
−73.796
68.774
1.00
19.30


ATOM
1472
CA
GLY
A
795
94.676
−72.597
68.942
1.00
19.27


ATOM
1473
C
GLY
A
795
93.846
−72.786
70.191
1.00
19.35


ATOM
1474
O
GLY
A
795
94.266
−73.482
71.111
1.00
19.33


ATOM
1475
N
ASP
A
796
92.678
−72.154
70.231
1.00
19.35


ATOM
1476
CA
ASP
A
796
91.757
−72.296
71.347
1.00
19.47


ATOM
1477
C
ASP
A
796
90.435
−71.687
70.912
1.00
19.60


ATOM
1478
O
ASP
A
796
90.384
−70.535
70.479
1.00
19.36


ATOM
1479
CB
ASP
A
796
92.271
−71.577
72.599
1.00
19.40


ATOM
1480
CG
ASP
A
796
91.432
−71.886
73.850
1.00
19.63


ATOM
1481
OD1
ASP
A
796
90.295
−72.402
73.727
1.00
19.59


ATOM
1482
OD2
ASP
A
796
91.907
−71.593
74.964
1.00
19.63


ATOM
1483
N
PHE
A
797
89.366
−72.467
71.009
1.00
19.84


ATOM
1484
CA
PHE
A
797
88.049
−71.966
70.642
1.00
20.33


ATOM
1485
C
PHE
A
797
87.583
−70.878
71.617
1.00
20.57


ATOM
1486
O
PHE
A
797
86.687
−70.081
71.302
1.00
20.68


ATOM
1487
CB
PHE
A
797
87.036
−73.120
70.593
1.00
20.36


ATOM
1488
CG
PHE
A
797
87.250
−74.064
69.434
1.00
20.46


ATOM
1489
CD1
PHE
A
797
88.087
−75.166
69.556
1.00
20.37


ATOM
1490
CD2
PHE
A
797
86.634
−73.827
68.205
1.00
20.67


ATOM
1491
CE1
PHE
A
797
88.311
−76.021
68.476
1.00
20.56


ATOM
1492
CE2
PHE
A
797
86.854
−74.679
67.115
1.00
20.55


ATOM
1493
CZ
PHE
A
797
87.692
−75.774
67.253
1.00
20.43


ATOM
1494
N
GLY
A
798
88.194
−70.850
72.799
1.00
20.82


ATOM
1495
CA
GLY
A
798
87.856
−69.846
73.796
1.00
21.20


ATOM
1496
C
GLY
A
798
86.379
−69.732
74.133
1.00
21.52


ATOM
1497
O
GLY
A
798
85.719
−70.743
74.392
1.00
21.50


ATOM
1498
N
LEU
A
799
85.857
−68.502
74.123
1.00
21.83


ATOM
1499
CA
LEU
A
799
84.452
−68.266
74.449
1.00
22.19


ATOM
1500
C
LEU
A
799
83.474
−68.970
73.513
1.00
22.46


ATOM
1501
O
LEU
A
799
82.257
−68.962
73.748
1.00
22.59


ATOM
1502
CB
LEU
A
799
84.155
−66.757
74.493
1.00
22.32


ATOM
1503
CG
LEU
A
799
84.372
−65.872
73.262
1.00
22.46


ATOM
1504
CD1
LEU
A
799
83.269
−66.130
72.232
1.00
22.40


ATOM
1505
CD2
LEU
A
799
84.363
−64.399
73.695
1.00
22.48


ATOM
1506
N
ALA
A
800
84.002
−69.584
72.459
1.00
22.59


ATOM
1507
CA
ALA
A
800
83.173
−70.302
71.506
1.00
22.78


ATOM
1508
C
ALA
A
800
83.117
−71.786
71.856
1.00
22.93


ATOM
1509
O
ALA
A
800
82.559
−72.588
71.106
1.00
22.98


ATOM
1510
CB
ALA
A
800
83.697
−70.112
70.088
1.00
22.84


ATOM
1511
N
ARG
A
801
83.710
−72.164
72.983
1.00
23.12


ATOM
1512
CA
ARG
A
801
83.643
−73.562
73.389
1.00
23.31


ATOM
1513
C
ARG
A
801
82.472
−73.736
74.346
1.00
23.40


ATOM
1514
O
ARG
A
801
82.228
−72.887
75.205
1.00
23.46


ATOM
1515
CB
ARG
A
801
84.929
−74.033
74.080
1.00
23.33


ATOM
1516
CG
ARG
A
801
84.791
−75.484
74.584
1.00
23.38


ATOM
1517
CD
ARG
A
801
86.085
−76.076
75.082
1.00
23.36


ATOM
1518
NE
ARG
A
801
87.116
−76.124
74.046
1.00
23.38


ATOM
1519
CZ
ARG
A
801
87.104
−76.940
72.997
1.00
23.39


ATOM
1520
NH1
ARG
A
801
86.104
−77.801
72.823
1.00
23.35


ATOM
1521
NH2
ARG
A
801
88.102
−76.896
72.121
1.00
23.18


ATOM
1522
N
ASP
A
802
81.759
−74.846
74.190
1.00
23.50


ATOM
1523
CA
ASP
A
802
80.597
−75.165
75.014
1.00
23.65


ATOM
1524
C
ASP
A
802
81.064
−75.640
76.385
1.00
23.66


ATOM
1525
O
ASP
A
802
80.713
−76.726
76.847
1.00
23.66


ATOM
1526
CB
ASP
A
802
79.783
−76.252
74.309
1.00
23.82


ATOM
1527
CG
ASP
A
802
78.481
−76.559
75.011
1.00
23.93


ATOM
1528
OD1
ASP
A
802
77.979
−75.682
75.751
1.00
24.03


ATOM
1529
OD2
ASP
A
802
77.958
−77.678
74.804
1.00
24.09


ATOM
1530
N
ILE
A
803
81.850
−74.791
77.032
1.00
23.64


ATOM
1531
CA
ILE
A
803
82.445
−75.077
78.329
1.00
23.73


ATOM
1532
C
ILE
A
803
81.489
−75.469
79.466
1.00
23.67


ATOM
1533
O
ILE
A
803
81.822
−76.307
80.302
1.00
23.64


ATOM
1534
CB
ILE
A
803
83.320
−73.873
78.754
1.00
23.85


ATOM
1535
CG1
ILE
A
803
84.379
−74.310
79.757
1.00
24.03


ATOM
1536
CG2
ILE
A
803
82.449
−72.774
79.337
1.00
23.86


ATOM
1537
CD1
ILE
A
803
85.300
−73.178
80.183
1.00
24.15


ATOM
1538
N
MET
A
804
80.301
−74.874
79.496
1.00
23.63


ATOM
1539
CA
MET
A
804
79.322
−75.164
80.544
1.00
23.66


ATOM
1540
C
MET
A
804
78.716
−76.572
80.488
1.00
23.50


ATOM
1541
O
MET
A
804
78.295
−77.104
81.513
1.00
23.55


ATOM
1542
CB
MET
A
804
78.185
−74.135
80.486
1.00
23.83


ATOM
1543
CG
MET
A
804
78.650
−72.674
80.538
1.00
24.27


ATOM
1544
SD
MET
A
804
79.564
−72.293
82.046
1.00
24.77


ATOM
1545
CE
MET
A
804
78.219
−72.031
83.211
1.00
24.61


ATOM
1546
N
ASN
A
805
78.663
−77.165
79.298
1.00
23.33


ATOM
1547
CA
ASN
A
805
78.074
−78.495
79.117
1.00
23.27


ATOM
1548
C
ASN
A
805
79.086
−79.568
78.737
1.00
23.30


ATOM
1549
O
ASN
A
805
78.712
−80.657
78.290
1.00
23.14


ATOM
1550
CB
ASN
A
805
76.991
−78.435
78.039
1.00
23.20


ATOM
1551
CG
ASN
A
805
75.955
−77.379
78.331
1.00
23.10


ATOM
1552
OD1
ASN
A
805
75.266
−77.446
79.345
1.00
23.12


ATOM
1553
ND2
ASN
A
805
75.851
−76.386
77.456
1.00
23.00


ATOM
1554
N
ASP
A
806
80.363
−79.248
78.907
1.00
23.31


ATOM
1555
CA
ASP
A
806
81.450
−80.168
78.591
1.00
23.46


ATOM
1556
C
ASP
A
806
81.994
−80.725
79.914
1.00
23.64


ATOM
1557
O
ASP
A
806
82.550
−79.983
80.722
1.00
23.51


ATOM
1558
CB
ASP
A
806
82.555
−79.419
77.844
1.00
23.27


ATOM
1559
CG
ASP
A
806
83.643
−80.341
77.332
1.00
23.16


ATOM
1560
OD1
ASP
A
806
83.983
−81.315
78.035
1.00
23.08


ATOM
1561
OD2
ASP
A
806
84.164
−80.082
76.229
1.00
23.03


ATOM
1562
N
SER
A
807
81.832
−82.029
80.126
1.00
23.94


ATOM
1563
CA
SER
A
807
82.287
−82.663
81.363
1.00
24.37


ATOM
1564
C
SER
A
807
83.807
−82.699
81.552
1.00
24.47


ATOM
1565
O
SER
A
807
84.288
−83.165
82.591
1.00
24.50


ATOM
1566
CB
SER
A
807
81.723
−84.084
81.464
1.00
24.56


ATOM
1567
OG
SER
A
807
82.149
−84.883
80.370
1.00
25.16


ATOM
1568
N
ASN
A
808
84.558
−82.221
80.558
1.00
24.58


ATOM
1569
CA
ASN
A
808
86.022
−82.175
80.657
1.00
24.74


ATOM
1570
C
ASN
A
808
86.436
−80.912
81.415
1.00
24.96


ATOM
1571
O
ASN
A
808
87.593
−80.752
81.812
1.00
24.89


ATOM
1572
CB
ASN
A
808
86.671
−82.172
79.271
1.00
24.82


ATOM
1573
CG
ASN
A
808
86.628
−83.533
78.603
1.00
24.91


ATOM
1574
OD1
ASN
A
808
86.957
−84.542
79.215
1.00
25.03


ATOM
1575
ND2
ASN
A
808
86.239
−83.562
77.337
1.00
25.07


ATOM
1576
N
TYR
A
809
85.483
−80.004
81.598
1.00
25.07


ATOM
1577
CA
TYR
A
809
85.750
−78.773
82.324
1.00
25.23


ATOM
1578
C
TYR
A
809
85.041
−78.841
83.666
1.00
25.90


ATOM
1579
O
TYR
A
809
83.821
−79.022
83.728
1.00
25.85


ATOM
1580
CB
TYR
A
809
85.283
−77.563
81.518
1.00
24.53


ATOM
1581
CG
TYR
A
809
86.099
−77.357
80.263
1.00
23.89


ATOM
1582
CD1
TYR
A
809
85.867
−78.125
79.121
1.00
23.60


ATOM
1583
CD2
TYR
A
809
87.126
−76.417
80.227
1.00
23.57


ATOM
1584
CE1
TYR
A
809
86.635
−77.959
77.971
1.00
23.33


ATOM
1585
CE2
TYR
A
809
87.904
−76.242
79.085
1.00
23.40


ATOM
1586
CZ
TYR
A
809
87.650
−77.012
77.962
1.00
23.32


ATOM
1587
OH
TYR
A
809
88.391
−76.822
76.829
1.00
23.06


ATOM
1588
N
ILE
A
810
85.825
−78.700
84.732
1.00
26.67


ATOM
1589
CA
ILE
A
810
85.337
−78.780
86.108
1.00
27.41


ATOM
1590
C
ILE
A
810
85.385
−77.452
86.860
1.00
27.96


ATOM
1591
O
ILE
A
810
86.352
−76.706
86.760
1.00
27.88


ATOM
1592
CB
ILE
A
810
86.170
−79.818
86.897
1.00
27.49


ATOM
1593
CG1
ILE
A
810
85.960
−81.210
86.299
1.00
27.59


ATOM
1594
CG2
ILE
A
810
85.810
−79.783
88.375
1.00
27.59


ATOM
1595
CD1
ILE
A
810
84.496
−81.630
86.215
1.00
27.72


ATOM
1596
N
VAL
A
811
84.338
−77.162
87.630
1.00
28.72


ATOM
1597
CA
VAL
A
811
84.310
−75.922
88.393
1.00
29.44


ATOM
1598
C
VAL
A
811
85.497
−75.936
89.352
1.00
29.93


ATOM
1599
O
VAL
A
811
85.689
−76.883
90.110
1.00
30.03


ATOM
1600
CB
VAL
A
811
83.006
−75.770
89.216
1.00
29.52


ATOM
1601
CG1
VAL
A
811
83.004
−74.426
89.940
1.00
29.69


ATOM
1602
CG2
VAL
A
811
81.799
−75.863
88.307
1.00
29.69


ATOM
1603
N
LYS
A
812
86.300
−74.886
89.289
1.00
30.49


ATOM
1604
CA
LYS
A
812
87.471
−74.754
90.138
1.00
31.05


ATOM
1605
C
LYS
A
812
87.481
−73.294
90.544
1.00
31.28


ATOM
1606
O
LYS
A
812
88.077
−72.451
89.870
1.00
31.43


ATOM
1607
CB
LYS
A
812
88.733
−75.113
89.342
1.00
31.29


ATOM
1608
CG
LYS
A
812
89.985
−75.392
90.180
1.00
31.58


ATOM
1609
CD
LYS
A
812
90.754
−74.120
90.491
1.00
31.74


ATOM
1610
CE
LYS
A
812
92.143
−74.449
91.008
1.00
31.81


ATOM
1611
NZ
LYS
A
812
92.914
−73.210
91.242
1.00
31.95


ATOM
1612
N
GLY
A
813
86.772
−72.999
91.631
1.00
31.48


ATOM
1613
CA
GLY
A
813
86.687
−71.640
92.124
1.00
31.56


ATOM
1614
C
GLY
A
813
85.979
−70.679
91.184
1.00
31.62


ATOM
1615
O
GLY
A
813
84.783
−70.791
90.922
1.00
31.70


ATOM
1616
N
ASN
A
814
86.741
−69.725
90.671
1.00
31.60


ATOM
1617
CA
ASN
A
814
86.222
−68.706
89.774
1.00
31.52


ATOM
1618
C
ASN
A
814
85.991
−69.177
88.340
1.00
31.19


ATOM
1619
O
ASN
A
814
85.569
−68.382
87.496
1.00
31.30


ATOM
1620
CB
ASN
A
814
87.195
−67.524
89.760
1.00
31.90


ATOM
1621
CG
ASN
A
814
88.586
−67.915
89.255
1.00
32.17


ATOM
1622
OD1
ASN
A
814
88.843
−67.928
88.047
1.00
32.36


ATOM
1623
ND2
ASN
A
814
89.484
−68.244
90.183
1.00
32.36


ATOM
1624
N
ALA
A
815
86.234
−70.457
88.057
1.00
30.75


ATOM
1625
CA
ALA
A
815
86.081
−70.931
86.680
1.00
30.09


ATOM
1626
C
ALA
A
815
85.813
−72.414
86.438
1.00
29.57


ATOM
1627
O
ALA
A
815
85.641
−73.207
87.363
1.00
29.61


ATOM
1628
CB
ALA
A
815
87.311
−70.516
85.888
1.00
30.11


ATOM
1629
N
ARG
A
816
85.774
−72.762
85.153
1.00
28.90


ATOM
1630
CA
ARG
A
816
85.567
−74.131
84.687
1.00
28.10


ATOM
1631
C
ARG
A
816
86.898
−74.511
84.032
1.00
27.32


ATOM
1632
O
ARG
A
816
87.248
−73.973
82.988
1.00
27.13


ATOM
1633
CB
ARG
A
816
84.451
−74.161
83.646
1.00
28.45


ATOM
1634
CG
ARG
A
816
83.138
−73.580
84.132
1.00
28.97


ATOM
1635
CD
ARG
A
816
82.076
−74.647
84.251
1.00
29.34


ATOM
1636
NE
ARG
A
816
80.958
−74.178
85.063
1.00
29.85


ATOM
1637
CZ
ARG
A
816
79.938
−74.939
85.428
1.00
29.94


ATOM
1638
NH1
ARG
A
816
78.963
−74.434
86.174
1.00
30.24


ATOM
1639
NH2
ARG
A
816
79.892
−76.205
85.040
1.00
30.13


ATOM
1640
N
LEU
A
817
87.633
−75.439
84.638
1.00
26.46


ATOM
1641
CA
LEU
A
817
88.946
−75.816
84.114
1.00
25.57


ATOM
1642
C
LEU
A
817
89.107
−77.270
83.674
1.00
24.81


ATOM
1643
O
LEU
A
817
88.487
−78.176
84.237
1.00
24.90


ATOM
1644
CB
LEU
A
817
90.020
−75.496
85.158
1.00
25.61


ATOM
1645
CG
LEU
A
817
90.074
−74.084
85.746
1.00
25.66


ATOM
1646
CD1
LEU
A
817
91.147
−74.041
86.819
1.00
25.73


ATOM
1647
CD2
LEU
A
817
90.369
−73.055
84.653
1.00
25.66


ATOM
1648
N
PRO
A
818
89.964
−77.508
82.660
1.00
24.05


ATOM
1649
CA
PRO
A
818
90.254
−78.836
82.103
1.00
23.35


ATOM
1650
C
PRO
A
818
91.250
−79.555
83.021
1.00
22.76


ATOM
1651
O
PRO
A
818
92.428
−79.721
82.682
1.00
22.37


ATOM
1652
CB
PRO
A
818
90.859
−78.500
80.744
1.00
23.48


ATOM
1653
CG
PRO
A
818
91.676
−77.275
81.073
1.00
23.60


ATOM
1654
CD
PRO
A
818
90.705
−76.463
81.925
1.00
23.90


ATOM
1655
N
VAL
A
819
90.761
−79.979
84.181
1.00
22.17


ATOM
1656
CA
VAL
A
819
91.598
−80.624
85.192
1.00
21.70


ATOM
1657
C
VAL
A
819
92.444
−81.827
84.786
1.00
21.38


ATOM
1658
O
VAL
A
819
93.580
−81.954
85.243
1.00
21.30


ATOM
1659
CB
VAL
A
819
90.753
−80.988
86.437
1.00
21.63


ATOM
1660
CG1
VAL
A
819
91.624
−81.644
87.497
1.00
21.64


ATOM
1661
CG2
VAL
A
819
90.106
−79.729
86.992
1.00
21.55


ATOM
1662
N
LYS
A
820
91.925
−82.711
83.940
1.00
21.01


ATOM
1663
CA
LYS
A
820
92.731
−83.864
83.546
1.00
20.73


ATOM
1664
C
LYS
A
820
93.917
−83.474
82.664
1.00
20.55


ATOM
1665
O
LYS
A
820
94.797
−84.292
82.412
1.00
20.44


ATOM
1666
CB
LYS
A
820
91.883
−84.911
82.828
1.00
20.72


ATOM
1667
CG
LYS
A
820
90.953
−85.693
83.735
1.00
20.71


ATOM
1668
CD
LYS
A
820
90.347
−86.868
82.988
1.00
20.79


ATOM
1669
CE
LYS
A
820
89.503
−87.714
83.919
1.00
20.97


ATOM
1670
NZ
LYS
A
820
89.009
−88.965
83.276
1.00
21.20


ATOM
1671
N
TRP
A
821
93.946
−82.224
82.204
1.00
20.34


ATOM
1672
CA
TRP
A
821
95.047
−81.750
81.359
1.00
20.35


ATOM
1673
C
TRP
A
821
95.994
−80.847
82.140
1.00
20.66


ATOM
1674
O
TRP
A
821
97.022
−80.416
81.628
1.00
20.57


ATOM
1675
CB
TRP
A
821
94.503
−80.963
80.159
1.00
19.67


ATOM
1676
CG
TRP
A
821
94.057
−81.822
79.023
1.00
18.97


ATOM
1677
CD1
TRP
A
821
94.778
−82.145
77.903
1.00
18.66


ATOM
1678
CD2
TRP
A
821
92.801
−82.502
78.904
1.00
18.56


ATOM
1679
NE1
TRP
A
821
94.045
−82.992
77.097
1.00
18.47


ATOM
1680
CE2
TRP
A
821
92.830
−83.225
77.688
1.00
18.52


ATOM
1681
CE3
TRP
A
821
91.654
−82.573
79.707
1.00
18.57


ATOM
1682
CZ2
TRP
A
821
91.756
−84.014
77.258
1.00
18.44


ATOM
1683
CZ3
TRP
A
821
90.584
−83.359
79.281
1.00
18.40


ATOM
1684
CH2
TRP
A
821
90.646
−84.069
78.066
1.00
18.39


ATOM
1685
N
MET
A
822
95.650
−80.580
83.392
1.00
21.13


ATOM
1686
CA
MET
A
822
96.438
−79.678
84.215
1.00
21.57


ATOM
1687
C
MET
A
822
97.553
−80.243
85.083
1.00
21.96


ATOM
1688
O
MET
A
822
97.462
−81.354
85.610
1.00
21.99


ATOM
1689
CB
MET
A
822
95.488
−78.855
85.078
1.00
21.57


ATOM
1690
CG
MET
A
822
94.739
−77.799
84.279
1.00
21.48


ATOM
1691
SD
MET
A
822
93.329
−77.131
85.159
1.00
21.51


ATOM
1692
CE
MET
A
822
94.099
−76.317
86.521
1.00
21.25


ATOM
1693
N
ALA
A
823
98.602
−79.437
85.229
1.00
22.40


ATOM
1694
CA
ALA
A
823
99.760
−79.783
86.039
1.00
22.99


ATOM
1695
C
ALA
A
823
99.349
−79.721
87.506
1.00
23.44


ATOM
1696
O
ALA
A
823
98.488
−78.925
87.876
1.00
23.40


ATOM
1697
CB
ALA
A
823
100.893
−78.795
85.777
1.00
22.76


ATOM
1698
N
PRO
A
824
99.959
−80.569
88.353
1.00
23.91


ATOM
1699
CA
PRO
A
824
99.695
−80.653
89.795
1.00
24.29


ATOM
1700
C
PRO
A
824
99.797
−79.300
90.502
1.00
24.66


ATOM
1701
O
PRO
A
824
98.961
−78.966
91.338
1.00
24.80


ATOM
1702
CB
PRO
A
824
100.766
−81.626
90.286
1.00
24.34


ATOM
1703
CG
PRO
A
824
100.983
−82.521
89.090
1.00
24.31


ATOM
1704
CD
PRO
A
824
101.011
−81.527
87.959
1.00
24.09


ATOM
1705
N
GLU
A
825
100.820
−78.521
90.168
1.00
24.98


ATOM
1706
CA
GLU
A
825
101.005
−77.224
90.812
1.00
25.39


ATOM
1707
C
GLU
A
825
99.919
−76.230
90.423
1.00
25.65


ATOM
1708
O
GLU
A
825
99.681
−75.245
91.137
1.00
25.75


ATOM
1709
CB
GLU
A
825
102.393
−76.643
90.496
1.00
25.38


ATOM
1710
CG
GLU
A
825
102.597
−76.175
89.058
1.00
25.46


ATOM
1711
CD
GLU
A
825
103.056
−77.277
88.109
1.00
25.46


ATOM
1712
OE1
GLU
A
825
103.043
−78.468
88.491
1.00
25.42


ATOM
1713
OE2
GLU
A
825
103.429
−76.937
86.967
1.00
25.54


ATOM
1714
N
SER
A
826
99.255
−76.480
89.296
1.00
25.73


ATOM
1715
CA
SER
A
826
98.184
−75.594
88.854
1.00
25.93


ATOM
1716
C
SER
A
826
96.899
−75.955
89.611
1.00
26.15


ATOM
1717
O
SER
A
826
96.156
−75.079
90.053
1.00
26.22


ATOM
1718
CB
SER
A
826
97.962
−75.730
87.337
1.00
25.76


ATOM
1719
OG
SER
A
826
99.131
−75.394
86.604
1.00
25.65


ATOM
1720
N
ILE
A
827
96.654
−77.252
89.765
1.00
26.36


ATOM
1721
CA
ILE
A
827
95.471
−77.731
90.460
1.00
26.73


ATOM
1722
C
ILE
A
827
95.523
−77.456
91.966
1.00
27.09


ATOM
1723
O
ILE
A
827
94.507
−77.124
92.579
1.00
27.07


ATOM
1724
CB
ILE
A
827
95.292
−79.254
90.265
1.00
26.66


ATOM
1725
CG1
ILE
A
827
95.133
−79.583
88.777
1.00
26.43


ATOM
1726
CG2
ILE
A
827
94.080
−79.737
91.050
1.00
26.75


ATOM
1727
CD1
ILE
A
827
95.135
−81.070
88.480
1.00
26.25


ATOM
1728
N
PHE
A
828
96.705
−77.591
92.561
1.00
27.38


ATOM
1729
CA
PHE
A
828
96.840
−77.376
93.998
1.00
27.75


ATOM
1730
C
PHE
A
828
97.227
−75.961
94.414
1.00
27.83


ATOM
1731
O
PHE
A
828
96.680
−75.425
95.378
1.00
28.01


ATOM
1732
CB
PHE
A
828
97.857
−78.356
94.592
1.00
27.92


ATOM
1733
CG
PHE
A
828
97.393
−79.782
94.610
1.00
28.18


ATOM
1734
CD1
PHE
A
828
97.332
−80.525
93.440
1.00
28.36


ATOM
1735
CD2
PHE
A
828
97.028
−80.391
95.810
1.00
28.32


ATOM
1736
CE1
PHE
A
828
96.917
−81.855
93.457
1.00
28.36


ATOM
1737
CE2
PHE
A
828
96.610
−81.724
95.839
1.00
28.44


ATOM
1738
CZ
PHE
A
828
96.557
−82.456
94.656
1.00
28.42


ATOM
1739
N
ASP
A
829
98.162
−75.354
93.696
1.00
27.86


ATOM
1740
CA
ASP
A
829
98.621
−74.016
94.046
1.00
27.85


ATOM
1741
C
ASP
A
829
98.171
−72.896
93.121
1.00
27.74


ATOM
1742
O
ASP
A
829
98.514
−71.739
93.345
1.00
27.64


ATOM
1743
CB
ASP
A
829
100.146
−74.007
94.133
1.00
28.13


ATOM
1744
CG
ASP
A
829
100.679
−75.126
94.995
1.00
28.41


ATOM
1745
OD1
ASP
A
829
100.111
−75.347
96.086
1.00
28.64


ATOM
1746
OD2
ASP
A
829
101.667
−75.780
94.587
1.00
28.67


ATOM
1747
N
CYS
A
830
97.409
−73.231
92.085
1.00
27.62


ATOM
1748
CA
CYS
A
830
96.938
−72.225
91.137
1.00
27.52


ATOM
1749
C
CYS
A
830
98.114
−71.516
90.483
1.00
27.20


ATOM
1750
O
CYS
A
830
98.038
−70.326
90.169
1.00
27.19


ATOM
1751
CB
CYS
A
830
96.066
−71.184
91.844
1.00
27.78


ATOM
1752
SG
CYS
A
830
94.703
−71.881
92.753
1.00
28.60


ATOM
1753
N
VAL
A
831
99.209
−72.242
90.297
1.00
26.85


ATOM
1754
CA
VAL
A
831
100.395
−71.682
89.664
1.00
26.48


ATOM
1755
C
VAL
A
831
100.413
−72.145
88.211
1.00
26.21


ATOM
1756
O
VAL
A
831
100.198
−73.320
87.932
1.00
26.14


ATOM
1757
CB
VAL
A
831
101.693
−72.161
90.369
1.00
26.59


ATOM
1758
CG1
VAL
A
831
102.923
−71.723
89.579
1.00
26.51


ATOM
1759
CG2
VAL
A
831
101.746
−71.601
91.784
1.00
26.46


ATOM
1760
N
TYR
A
832
100.666
−71.218
87.296
1.00
25.92


ATOM
1761
CA
TYR
A
832
100.713
−71.544
85.873
1.00
25.68


ATOM
1762
C
TYR
A
832
101.938
−70.941
85.199
1.00
25.49


ATOM
1763
O
TYR
A
832
102.191
−69.747
85.314
1.00
25.68


ATOM
1764
CB
TYR
A
832
99.461
−71.029
85.167
1.00
25.63


ATOM
1765
CG
TYR
A
832
98.175
−71.643
85.665
1.00
25.58


ATOM
1766
CD1
TYR
A
832
97.510
−71.122
86.775
1.00
25.56


ATOM
1767
CD2
TYR
A
832
97.621
−72.745
85.022
1.00
25.56


ATOM
1768
CE1
TYR
A
832
96.315
−71.686
87.229
1.00
25.56


ATOM
1769
CE2
TYR
A
832
96.440
−73.317
85.465
1.00
25.59


ATOM
1770
CZ
TYR
A
832
95.790
−72.783
86.569
1.00
25.62


ATOM
1771
OH
TYR
A
832
94.618
−73.357
87.000
1.00
25.71


ATOM
1772
N
THR
A
833
102.695
−71.774
84.493
1.00
25.11


ATOM
1773
CA
THR
A
833
103.889
−71.314
83.787
1.00
24.58


ATOM
1774
C
THR
A
833
103.951
−72.043
82.450
1.00
24.32


ATOM
1775
O
THR
A
833
103.060
−72.825
82.123
1.00
24.13


ATOM
1776
CB
THR
A
833
105.165
−71.663
84.557
1.00
24.54


ATOM
1777
OG1
THR
A
833
105.325
−73.085
84.572
1.00
24.58


ATOM
1778
CG2
THR
A
833
105.087
−71.147
85.995
1.00
24.73


ATOM
1779
N
VAL
A
834
105.004
−71.787
81.679
1.00
24.03


ATOM
1780
CA
VAL
A
834
105.168
−72.463
80.400
1.00
23.70


ATOM
1781
C
VAL
A
834
105.318
−73.949
80.699
1.00
23.47


ATOM
1782
O
VAL
A
834
104.824
−74.791
79.946
1.00
23.31


ATOM
1783
CB
VAL
A
834
106.423
−71.953
79.638
1.00
23.83


ATOM
1784
CG1
VAL
A
834
106.800
−72.932
78.524
1.00
23.83


ATOM
1785
CG2
VAL
A
834
106.150
−70.584
79.059
1.00
23.85


ATOM
1786
N
GLN
A
835
105.978
−74.265
81.816
1.00
23.21


ATOM
1787
CA
GLN
A
835
106.182
−75.661
82.213
1.00
23.01


ATOM
1788
C
GLN
A
835
104.842
−76.301
82.497
1.00
22.49


ATOM
1789
O
GLN
A
835
104.687
−77.523
82.435
1.00
22.31


ATOM
1790
CB
GLN
A
835
107.052
−75.759
83.469
1.00
23.55


ATOM
1791
CG
GLN
A
835
108.511
−75.476
83.232
1.00
24.46


ATOM
1792
CD
GLN
A
835
108.741
−74.123
82.623
1.00
24.99


ATOM
1793
OE1
GLN
A
835
109.467
−73.991
81.633
1.00
25.63


ATOM
1794
NE2
GLN
A
835
108.122
−73.096
83.203
1.00
25.52


ATOM
1795
N
SER
A
836
103.881
−75.453
82.830
1.00
21.95


ATOM
1796
CA
SER
A
836
102.531
−75.897
83.124
1.00
21.49


ATOM
1797
C
SER
A
836
101.915
−76.368
81.803
1.00
20.77


ATOM
1798
O
SER
A
836
101.267
−77.422
81.737
1.00
20.70


ATOM
1799
CB
SER
A
836
101.752
−74.721
83.717
1.00
21.65


ATOM
1800
OG
SER
A
836
100.504
−75.138
84.174
1.00
22.80


ATOM
1801
N
ASP
A
837
102.118
−75.580
80.753
1.00
19.95


ATOM
1802
CA
ASP
A
837
101.621
−75.943
79.427
1.00
19.32


ATOM
1803
C
ASP
A
837
102.356
−77.181
78.911
1.00
19.02


ATOM
1804
O
ASP
A
837
101.799
−77.974
78.161
1.00
18.90


ATOM
1805
CB
ASP
A
837
101.800
−74.796
78.434
1.00
18.92


ATOM
1806
CG
ASP
A
837
100.738
−73.719
78.583
1.00
18.82


ATOM
1807
OD1
ASP
A
837
99.645
−74.010
79.126
1.00
18.53


ATOM
1808
OD2
ASP
A
837
100.993
−72.583
78.134
1.00
18.71


ATOM
1809
N
VAL
A
838
103.618
−77.332
79.292
1.00
18.76


ATOM
1810
CA
VAL
A
838
104.382
−78.503
78.874
1.00
18.51


ATOM
1811
C
VAL
A
838
103.707
−79.757
79.419
1.00
18.25


ATOM
1812
O
VAL
A
838
103.571
−80.763
78.711
1.00
18.14


ATOM
1813
CB
VAL
A
838
105.838
−78.433
79.374
1.00
18.51


ATOM
1814
CG1
VAL
A
838
106.553
−79.760
79.105
1.00
18.58


ATOM
1815
CG2
VAL
A
838
106.560
−77.307
78.662
1.00
18.66


ATOM
1816
N
TRP
A
839
103.269
−79.701
80.674
1.00
17.96


ATOM
1817
CA
TRP
A
839
102.587
−80.849
81.265
1.00
17.58


ATOM
1818
C
TRP
A
839
101.362
−81.174
80.418
1.00
17.29


ATOM
1819
O
TRP
A
839
101.150
−82.322
80.048
1.00
17.21


ATOM
1820
CB
TRP
A
839
102.168
−80.561
82.720
1.00
17.73


ATOM
1821
CG
TRP
A
839
101.293
−81.636
83.344
1.00
17.93


ATOM
1822
CD1
TRP
A
839
99.995
−81.936
83.015
1.00
17.92


ATOM
1823
CD2
TRP
A
839
101.665
−82.569
84.376
1.00
17.92


ATOM
1824
NE1
TRP
A
839
99.547
−82.987
83.769
1.00
17.95


ATOM
1825
CE2
TRP
A
839
100.545
−83.397
84.612
1.00
17.95


ATOM
1826
CE3
TRP
A
839
102.832
−82.784
85.118
1.00
17.95


ATOM
1827
CZ2
TRP
A
839
100.557
−84.430
85.559
1.00
18.01


ATOM
1828
CZ3
TRP
A
839
102.848
−83.813
86.065
1.00
17.92


ATOM
1829
CH2
TRP
A
839
101.712
−84.625
86.275
1.00
18.05


ATOM
1830
N
SER
A
840
100.562
−80.160
80.101
1.00
16.92


ATOM
1831
CA
SER
A
840
99.362
−80.368
79.304
1.00
16.67


ATOM
1832
C
SER
A
840
99.751
−80.933
77.936
1.00
16.49


ATOM
1833
O
SER
A
840
99.070
−81.807
77.402
1.00
16.40


ATOM
1834
CB
SER
A
840
98.599
−79.050
79.131
1.00
16.70


ATOM
1835
OG
SER
A
840
98.259
−78.491
80.388
1.00
16.79


ATOM
1836
N
TYR
A
841
100.854
−80.442
77.376
1.00
16.13


ATOM
1837
CA
TYR
A
841
101.301
−80.947
76.080
1.00
15.91


ATOM
1838
C
TYR
A
841
101.559
−82.451
76.188
1.00
15.75


ATOM
1839
O
TYR
A
841
101.351
−83.204
75.230
1.00
15.47


ATOM
1840
CB
TYR
A
841
102.590
−80.255
75.633
1.00
15.75


ATOM
1841
CG
TYR
A
841
103.154
−80.863
74.379
1.00
15.61


ATOM
1842
CD1
TYR
A
841
102.667
−80.498
73.130
1.00
15.63


ATOM
1843
CD2
TYR
A
841
104.137
−81.854
74.443
1.00
15.66


ATOM
1844
CE1
TYR
A
841
103.140
−81.107
71.971
1.00
15.60


ATOM
1845
CE2
TYR
A
841
104.621
−82.470
73.287
1.00
15.70


ATOM
1846
CZ
TYR
A
841
104.117
−82.092
72.060
1.00
15.63


ATOM
1847
OH
TYR
A
841
104.577
−82.698
70.918
1.00
15.72


ATOM
1848
N
GLY
A
842
102.025
−82.878
77.357
1.00
15.77


ATOM
1849
CA
GLY
A
842
102.285
−84.290
77.564
1.00
15.74


ATOM
1850
C
GLY
A
842
100.974
−85.062
77.494
1.00
15.86


ATOM
1851
O
GLY
A
842
100.911
−86.175
76.953
1.00
15.77


ATOM
1852
N
ILE
A
843
99.916
−84.473
78.049
1.00
15.91


ATOM
1853
CA
ILE
A
843
98.614
−85.128
78.027
1.00
15.81


ATOM
1854
C
ILE
A
843
98.138
−85.210
76.570
1.00
15.95


ATOM
1855
O
ILE
A
843
97.628
−86.238
76.140
1.00
15.72


ATOM
1856
CB
ILE
A
843
97.572
−84.358
78.879
1.00
15.84


ATOM
1857
CG1
ILE
A
843
98.047
−84.266
80.341
1.00
15.76


ATOM
1858
CG2
ILE
A
843
96.201
−85.079
78.806
1.00
15.76


ATOM
1859
CD1
ILE
A
843
98.201
−85.622
81.049
1.00
15.69


ATOM
1860
N
LEU
A
844
98.326
−84.120
75.828
1.00
16.23


ATOM
1861
CA
LEU
A
844
97.939
−84.026
74.417
1.00
16.54


ATOM
1862
C
LEU
A
844
98.678
−85.090
73.604
1.00
16.84


ATOM
1863
O
LEU
A
844
98.096
−85.745
72.731
1.00
16.98


ATOM
1864
CB
LEU
A
844
98.273
−82.619
73.879
1.00
16.67


ATOM
1865
CG
LEU
A
844
97.968
−82.246
72.420
1.00
16.87


ATOM
1866
CD1
LEU
A
844
97.961
−80.720
72.249
1.00
17.04


ATOM
1867
CD2
LEU
A
844
98.996
−82.876
71.507
1.00
16.97


ATOM
1868
N
LEU
A
845
99.966
−85.258
73.889
1.00
16.97


ATOM
1869
CA
LEU
A
845
100.753
−86.245
73.176
1.00
17.17


ATOM
1870
C
LEU
A
845
100.136
−87.621
73.418
1.00
17.19


ATOM
1871
O
LEU
A
845
100.049
−88.435
72.496
1.00
17.02


ATOM
1872
CB
LEU
A
845
102.208
−86.203
73.647
1.00
17.45


ATOM
1873
CG
LEU
A
845
103.271
−86.890
72.785
1.00
17.81


ATOM
1874
CD1
LEU
A
845
103.236
−86.348
71.355
1.00
17.74


ATOM
1875
CD2
LEU
A
845
104.637
−86.641
73.400
1.00
17.88


ATOM
1876
N
TRP
A
846
99.683
−87.864
74.651
1.00
17.11


ATOM
1877
CA
TRP
A
846
99.059
−89.137
75.003
1.00
17.11


ATOM
1878
C
TRP
A
846
97.765
−89.319
74.208
1.00
17.20


ATOM
1879
O
TRP
A
846
97.442
−90.435
73.797
1.00
17.07


ATOM
1880
CB
TRP
A
846
98.750
−89.200
76.505
1.00
16.92


ATOM
1881
CG
TRP
A
846
98.300
−90.564
76.982
1.00
16.74


ATOM
1882
CD1
TRP
A
846
99.100
−91.593
77.404
1.00
16.65


ATOM
1883
CD2
TRP
A
846
96.947
−91.039
77.083
1.00
16.54


ATOM
1884
NE1
TRP
A
846
98.329
−92.673
77.765
1.00
16.65


ATOM
1885
CE2
TRP
A
846
97.005
−92.362
77.576
1.00
16.49


ATOM
1886
CE3
TRP
A
846
95.694
−90.474
76.806
1.00
16.51


ATOM
1887
CZ2
TRP
A
846
95.858
−93.131
77.800
1.00
16.37


ATOM
1888
CZ3
TRP
A
846
94.540
−91.247
77.030
1.00
16.50


ATOM
1889
CH2
TRP
A
846
94.639
−92.561
77.523
1.00
16.42


ATOM
1890
N
GLU
A
847
97.022
−88.231
73.996
1.00
17.31


ATOM
1891
CA
GLU
A
847
95.784
−88.303
73.215
1.00
17.63


ATOM
1892
C
GLU
A
847
96.118
−88.669
71.771
1.00
17.80


ATOM
1893
O
GLU
A
847
95.403
−89.447
71.123
1.00
17.91


ATOM
1894
CB
GLU
A
847
95.053
−86.960
73.186
1.00
17.70


ATOM
1895
CG
GLU
A
847
94.542
−86.434
74.513
1.00
17.87


ATOM
1896
CD
GLU
A
847
93.764
−85.159
74.315
1.00
17.98


ATOM
1897
OE1
GLU
A
847
92.588
−85.241
73.902
1.00
18.29


ATOM
1898
OE2
GLU
A
847
94.335
−84.071
74.545
1.00
18.16


ATOM
1899
N
ILE
A
848
97.194
−88.091
71.253
1.00
17.92


ATOM
1900
CA
ILE
A
848
97.584
−88.381
69.877
1.00
18.20


ATOM
1901
C
ILE
A
848
97.941
−89.852
69.714
1.00
18.43


ATOM
1902
O
ILE
A
848
97.429
−90.519
68.820
1.00
18.38


ATOM
1903
CB
ILE
A
848
98.809
−87.545
69.419
1.00
18.15


ATOM
1904
CG1
ILE
A
848
98.431
−86.065
69.279
1.00
17.85


ATOM
1905
CG2
ILE
A
848
99.317
−88.074
68.078
1.00
18.25


ATOM
1906
CD1
ILE
A
848
99.622
−85.144
68.994
1.00
17.82


ATOM
1907
N
PHE
A
849
98.812
−90.364
70.579
1.00
18.77


ATOM
1908
CA
PHE
A
849
99.224
−91.758
70.443
1.00
19.20


ATOM
1909
C
PHE
A
849
98.287
−92.839
70.980
1.00
19.49


ATOM
1910
O
PHE
A
849
98.643
−94.020
70.987
1.00
19.56


ATOM
1911
CB
PHE
A
849
100.636
−91.947
70.995
1.00
19.24


ATOM
1912
CG
PHE
A
849
101.700
−91.332
70.119
1.00
19.37


ATOM
1913
CD1
PHE
A
849
102.026
−89.988
70.237
1.00
19.40


ATOM
1914
CD2
PHE
A
849
102.308
−92.084
69.120
1.00
19.39


ATOM
1915
CE1
PHE
A
849
102.942
−89.394
69.369
1.00
19.47


ATOM
1916
CE2
PHE
A
849
103.223
−91.507
68.245
1.00
19.52


ATOM
1917
CZ
PHE
A
849
103.540
−90.160
68.367
1.00
19.48


ATOM
1918
N
SER
A
850
97.097
−92.435
71.414
1.00
19.86


ATOM
1919
CA
SER
A
850
96.074
−93.371
71.889
1.00
20.21


ATOM
1920
C
SER
A
850
94.896
−93.192
70.923
1.00
20.48


ATOM
1921
O
SER
A
850
93.819
−93.795
71.070
1.00
20.33


ATOM
1922
CB
SER
A
850
95.633
−93.023
73.318
1.00
20.19


ATOM
1923
OG
SER
A
850
94.857
−91.836
73.343
1.00
20.22


ATOM
1924
N
LEU
A
851
95.131
−92.349
69.926
1.00
20.69


ATOM
1925
CA
LEU
A
851
94.148
−92.020
68.905
1.00
21.02


ATOM
1926
C
LEU
A
851
92.843
−91.445
69.459
1.00
21.20


ATOM
1927
O
LEU
A
851
91.759
−91.829
69.035
1.00
21.16


ATOM
1928
CB
LEU
A
851
93.856
−93.245
68.009
1.00
21.07


ATOM
1929
CG
LEU
A
851
95.032
−93.801
67.183
1.00
21.07


ATOM
1930
CD1
LEU
A
851
94.525
−94.891
66.245
1.00
21.04


ATOM
1931
CD2
LEU
A
851
95.686
−92.691
66.375
1.00
20.96


ATOM
1932
N
GLY
A
852
92.948
−90.530
70.416
1.00
21.40


ATOM
1933
CA
GLY
A
852
91.752
−89.895
70.945
1.00
21.69


ATOM
1934
C
GLY
A
852
91.066
−90.452
72.176
1.00
21.95


ATOM
1935
O
GLY
A
852
89.889
−90.160
72.398
1.00
21.89


ATOM
1936
N
LEU
A
853
91.760
−91.262
72.965
1.00
22.19


ATOM
1937
CA
LEU
A
853
91.161
−91.783
74.186
1.00
22.50


ATOM
1938
C
LEU
A
853
91.081
−90.654
75.205
1.00
22.85


ATOM
1939
O
LEU
A
853
91.890
−89.722
75.179
1.00
22.77


ATOM
1940
CB
LEU
A
853
92.001
−92.922
74.776
1.00
22.32


ATOM
1941
CG
LEU
A
853
91.968
−94.277
74.062
1.00
22.28


ATOM
1942
CD1
LEU
A
853
92.687
−95.325
74.921
1.00
22.20


ATOM
1943
CD2
LEU
A
853
90.520
−94.695
73.823
1.00
22.18


ATOM
1944
N
ASN
A
854
90.090
−90.738
76.090
1.00
23.25


ATOM
1945
CA
ASN
A
854
89.908
−89.758
77.157
1.00
23.58


ATOM
1946
C
ASN
A
854
91.006
−90.028
78.179
1.00
23.67


ATOM
1947
O
ASN
A
854
91.222
−91.176
78.564
1.00
23.60


ATOM
1948
CB
ASN
A
854
88.548
−89.955
77.835
1.00
23.90


ATOM
1949
CG
ASN
A
854
87.385
−89.780
76.882
1.00
24.33


ATOM
1950
OD1
ASN
A
854
87.151
−88.687
76.360
1.00
24.68


ATOM
1951
ND2
ASN
A
854
86.639
−90.861
76.650
1.00
24.51


ATOM
1952
N
PRO
A
855
91.718
−88.982
78.629
1.00
23.81


ATOM
1953
CA
PRO
A
855
92.793
−89.163
79.614
1.00
24.10


ATOM
1954
C
PRO
A
855
92.298
−89.835
80.903
1.00
24.35


ATOM
1955
O
PRO
A
855
91.160
−89.630
81.312
1.00
24.37


ATOM
1956
CB
PRO
A
855
93.292
−87.734
79.846
1.00
23.96


ATOM
1957
CG
PRO
A
855
93.081
−87.097
78.497
1.00
23.90


ATOM
1958
CD
PRO
A
855
91.691
−87.596
78.132
1.00
23.84


ATOM
1959
N
TYR
A
856
93.161
−90.633
81.527
1.00
24.73


ATOM
1960
CA
TYR
A
856
92.825
−91.362
82.754
1.00
25.22


ATOM
1961
C
TYR
A
856
91.493
−92.092
82.577
1.00
25.61


ATOM
1962
O
TYR
A
856
90.561
−91.913
83.367
1.00
25.55


ATOM
1963
CB
TYR
A
856
92.736
−90.409
83.950
1.00
25.18


ATOM
1964
CG
TYR
A
856
93.958
−89.528
84.131
1.00
25.34


ATOM
1965
CD1
TYR
A
856
94.003
−88.248
83.583
1.00
25.39


ATOM
1966
CD2
TYR
A
856
95.082
−89.990
84.818
1.00
25.42


ATOM
1967
CE1
TYR
A
856
95.143
−87.445
83.711
1.00
25.59


ATOM
1968
CE2
TYR
A
856
96.228
−89.198
84.950
1.00
25.55


ATOM
1969
CZ
TYR
A
856
96.246
−87.930
84.393
1.00
25.55


ATOM
1970
OH
TYR
A
856
97.368
−87.146
84.503
1.00
25.91


ATOM
1971
N
PRO
A
857
91.397
−92.940
81.542
1.00
26.08


ATOM
1972
CA
PRO
A
857
90.172
−93.687
81.259
1.00
26.54


ATOM
1973
C
PRO
A
857
89.537
−94.375
82.457
1.00
26.96


ATOM
1974
O
PRO
A
857
90.213
−95.059
83.227
1.00
26.90


ATOM
1975
CB
PRO
A
857
90.606
−94.671
80.168
1.00
26.46


ATOM
1976
CG
PRO
A
857
92.076
−94.827
80.391
1.00
26.41


ATOM
1977
CD
PRO
A
857
92.504
−93.416
80.692
1.00
26.16


ATOM
1978
N
GLY
A
858
88.229
−94.168
82.606
1.00
27.44


ATOM
1979
CA
GLY
A
858
87.492
−94.778
83.697
1.00
28.02


ATOM
1980
C
GLY
A
858
87.704
−94.153
85.065
1.00
28.44


ATOM
1981
O
GLY
A
858
87.077
−94.578
86.034
1.00
28.45


ATOM
1982
N
ILE
A
859
88.576
−93.152
85.160
1.00
28.79


ATOM
1983
CA
ILE
A
859
88.842
−92.505
86.445
1.00
29.23


ATOM
1984
C
ILE
A
859
88.115
−91.168
86.568
1.00
29.60


ATOM
1985
O
ILE
A
859
88.367
−90.239
85.799
1.00
29.60


ATOM
1986
CB
ILE
A
859
90.351
−92.234
86.649
1.00
29.24


ATOM
1987
CG1
ILE
A
859
91.148
−93.534
86.539
1.00
29.09


ATOM
1988
CG2
ILE
A
859
90.578
−91.588
88.014
1.00
29.30


ATOM
1989
CD1
ILE
A
859
92.655
−93.340
86.664
1.00
29.10


ATOM
1990
N
LEU
A
860
87.221
−91.069
87.546
1.00
30.04


ATOM
1991
CA
LEU
A
860
86.480
−89.831
87.761
1.00
30.52


ATOM
1992
C
LEU
A
860
87.332
−88.817
88.510
1.00
30.76


ATOM
1993
O
LEU
A
860
88.191
−89.184
89.314
1.00
30.81


ATOM
1994
CB
LEU
A
860
85.202
−90.097
88.560
1.00
30.64


ATOM
1995
CG
LEU
A
860
84.096
−90.911
87.880
1.00
30.78


ATOM
1996
CD1
LEU
A
860
82.852
−90.898
88.764
1.00
30.84


ATOM
1997
CD2
LEU
A
860
83.774
−90.318
86.511
1.00
30.81


ATOM
1998
N
VAL
A
861
87.088
−87.541
88.234
1.00
31.12


ATOM
1999
CA
VAL
A
861
87.810
−86.461
88.884
1.00
31.64


ATOM
2000
C
VAL
A
861
87.209
−86.190
90.264
1.00
31.99


ATOM
2001
O
VAL
A
861
86.122
−85.628
90.383
1.00
32.05


ATOM
2002
CB
VAL
A
861
87.744
−85.156
88.052
1.00
31.58


ATOM
2003
CG1
VAL
A
861
88.454
−84.033
88.793
1.00
31.58


ATOM
2004
CG2
VAL
A
861
88.385
−85.367
86.691
1.00
31.59


ATOM
2005
N
ASN
A
862
87.923
−86.607
91.302
1.00
32.45


ATOM
2006
CA
ASN
A
862
87.492
−86.406
92.679
1.00
32.87


ATOM
2007
C
ASN
A
862
88.738
−86.383
93.542
1.00
33.08


ATOM
2008
O
ASN
A
862
89.851
−86.357
93.022
1.00
33.09


ATOM
2009
CB
ASN
A
862
86.564
−87.537
93.137
1.00
33.01


ATOM
2010
CG
ASN
A
862
87.165
−88.914
92.920
1.00
33.25


ATOM
2011
OD1
ASN
A
862
88.354
−89.141
93.175
1.00
33.30


ATOM
2012
ND2
ASN
A
862
86.339
−89.850
92.457
1.00
33.36


ATOM
2013
N
SER
A
863
88.552
−86.405
94.857
1.00
33.37


ATOM
2014
CA
SER
A
863
89.678
−86.381
95.785
1.00
33.63


ATOM
2015
C
SER
A
863
90.746
−87.414
95.444
1.00
33.68


ATOM
2016
O
SER
A
863
91.928
−87.085
95.355
1.00
33.73


ATOM
2017
CB
SER
A
863
89.189
−86.614
97.219
1.00
33.70


ATOM
2018
OG
SER
A
863
88.572
−87.882
97.345
1.00
34.01


ATOM
2019
N
LYS
A
864
90.334
−88.662
95.247
1.00
33.78


ATOM
2020
CA
LYS
A
864
91.285
−89.719
94.930
1.00
33.85


ATOM
2021
C
LYS
A
864
92.122
−89.378
93.699
1.00
33.66


ATOM
2022
O
LYS
A
864
93.346
−89.538
93.711
1.00
33.72


ATOM
2023
CB
LYS
A
864
90.551
−91.047
94.729
1.00
34.18


ATOM
2024
CG
LYS
A
864
89.744
−91.462
95.955
1.00
34.67


ATOM
2025
CD
LYS
A
864
89.156
−92.860
95.842
1.00
35.03


ATOM
2026
CE
LYS
A
864
88.464
−93.237
97.156
1.00
35.25


ATOM
2027
NZ
LYS
A
864
88.025
−94.662
97.202
1.00
35.44


ATOM
2028
N
PHE
A
865
91.469
−88.898
92.645
1.00
33.39


ATOM
2029
CA
PHE
A
865
92.184
−88.536
91.426
1.00
33.10


ATOM
2030
C
PHE
A
865
93.310
−87.563
91.747
1.00
32.94


ATOM
2031
O
PHE
A
865
94.453
−87.764
91.332
1.00
32.87


ATOM
2032
CB
PHE
A
865
91.247
−87.886
90.409
1.00
33.10


ATOM
2033
CG
PHE
A
865
91.967
−87.310
89.219
1.00
33.03


ATOM
2034
CD1
PHE
A
865
92.476
−88.142
88.230
1.00
33.03


ATOM
2035
CD2
PHE
A
865
92.197
−85.939
89.125
1.00
33.07


ATOM
2036
CE1
PHE
A
865
93.206
−87.617
87.164
1.00
32.98


ATOM
2037
CE2
PHE
A
865
92.929
−85.404
88.058
1.00
33.09


ATOM
2038
CZ
PHE
A
865
93.433
−86.247
87.080
1.00
32.93


ATOM
2039
N
TYR
A
866
92.977
−86.505
92.481
1.00
32.78


ATOM
2040
CA
TYR
A
866
93.960
−85.499
92.868
1.00
32.69


ATOM
2041
C
TYR
A
866
95.129
−86.098
93.643
1.00
32.57


ATOM
2042
O
TYR
A
866
96.276
−85.723
93.422
1.00
32.57


ATOM
2043
CB
TYR
A
866
93.297
−84.400
93.699
1.00
32.73


ATOM
2044
CG
TYR
A
866
92.307
−83.572
92.913
1.00
32.76


ATOM
2045
CD1
TYR
A
866
92.665
−83.015
91.690
1.00
32.80


ATOM
2046
CD2
TYR
A
866
91.016
−83.340
93.391
1.00
32.79


ATOM
2047
CE1
TYR
A
866
91.769
−82.251
90.958
1.00
32.90


ATOM
2048
CE2
TYR
A
866
90.106
−82.571
92.663
1.00
32.74


ATOM
2049
CZ
TYR
A
866
90.492
−82.033
91.447
1.00
32.83


ATOM
2050
OH
TYR
A
866
89.615
−81.283
90.698
1.00
32.91


ATOM
2051
N
LYS
A
867
94.840
−87.027
94.551
1.00
32.53


ATOM
2052
CA
LYS
A
867
95.899
−87.663
95.329
1.00
32.40


ATOM
2053
C
LYS
A
867
96.843
−88.405
94.390
1.00
32.13


ATOM
2054
O
LYS
A
867
98.067
−88.290
94.501
1.00
32.12


ATOM
2055
CB
LYS
A
867
95.323
−88.660
96.335
1.00
32.65


ATOM
2056
CG
LYS
A
867
96.416
−89.371
97.138
1.00
33.14


ATOM
2057
CD
LYS
A
867
95.890
−90.552
97.941
1.00
33.37


ATOM
2058
CE
LYS
A
867
97.046
−91.327
98.576
1.00
33.57


ATOM
2059
NZ
LYS
A
867
96.578
−92.598
99.217
1.00
33.66


ATOM
2060
N
LEU
A
868
96.260
−89.173
93.474
1.00
31.83


ATOM
2061
CA
LEU
A
868
97.031
−89.942
92.504
1.00
31.55


ATOM
2062
C
LEU
A
868
98.077
−89.082
91.816
1.00
31.29


ATOM
2063
O
LEU
A
868
99.268
−89.380
91.868
1.00
31.23


ATOM
2064
CB
LEU
A
868
96.109
−90.541
91.438
1.00
31.64


ATOM
2065
CG
LEU
A
868
95.220
−91.742
91.779
1.00
31.73


ATOM
2066
CD1
LEU
A
868
94.349
−92.058
90.570
1.00
31.78


ATOM
2067
CD2
LEU
A
868
96.068
−92.952
92.148
1.00
31.70


ATOM
2068
N
VAL
A
869
97.623
−88.016
91.168
1.00
31.03


ATOM
2069
CA
VAL
A
869
98.517
−87.118
90.446
1.00
30.88


ATOM
2070
C
VAL
A
869
99.574
−86.533
91.365
1.00
30.65


ATOM
2071
O
VAL
A
869
100.765
−86.549
91.047
1.00
30.67


ATOM
2072
CB
VAL
A
869
97.735
−85.957
89.790
1.00
30.92


ATOM
2073
CG1
VAL
A
869
98.684
−85.058
89.020
1.00
30.93


ATOM
2074
CG2
VAL
A
869
96.662
−86.511
88.878
1.00
30.98


ATOM
2075
N
LYS
A
870
99.130
−86.018
92.505
1.00
30.35


ATOM
2076
CA
LYS
A
870
100.035
−85.424
93.476
1.00
30.04


ATOM
2077
C
LYS
A
870
101.120
−86.438
93.825
1.00
29.55


ATOM
2078
O
LYS
A
870
102.294
−86.088
93.926
1.00
29.54


ATOM
2079
CB
LYS
A
870
99.268
−85.031
94.742
1.00
30.40


ATOM
2080
CG
LYS
A
870
100.075
−84.193
95.721
1.00
30.97


ATOM
2081
CD
LYS
A
870
100.424
−82.845
95.102
1.00
31.42


ATOM
2082
CE
LYS
A
870
101.182
−81.947
96.077
1.00
31.64


ATOM
2083
NZ
LYS
A
870
101.515
−80.634
95.446
1.00
31.98


ATOM
2084
N
ASP
A
871
100.719
−87.698
93.980
1.00
28.88


ATOM
2085
CA
ASP
A
871
101.650
−88.767
94.321
1.00
28.18


ATOM
2086
C
ASP
A
871
102.532
−89.254
93.169
1.00
27.60


ATOM
2087
O
ASP
A
871
103.344
−90.163
93.344
1.00
27.60


ATOM
2088
CB
ASP
A
871
100.896
−89.958
94.916
1.00
28.34


ATOM
2089
CG
ASP
A
871
100.388
−89.686
96.324
1.00
28.46


ATOM
2090
OD1
ASP
A
871
100.899
−88.753
96.974
1.00
28.53


ATOM
2091
OD2
ASP
A
871
99.486
−90.418
96.782
1.00
28.63


ATOM
2092
N
GLY
A
872
102.369
−88.669
91.991
1.00
26.79


ATOM
2093
CA
GLY
A
872
103.207
−89.071
90.876
1.00
25.81


ATOM
2094
C
GLY
A
872
102.642
−90.105
89.928
1.00
25.10


ATOM
2095
O
GLY
A
872
103.384
−90.673
89.126
1.00
24.89


ATOM
2096
N
TYR
A
873
101.336
−90.354
90.012
1.00
24.38


ATOM
2097
CA
TYR
A
873
100.687
−91.311
89.123
1.00
23.67


ATOM
2098
C
TYR
A
873
100.790
−90.811
87.685
1.00
23.28


ATOM
2099
O
TYR
A
873
100.649
−89.619
87.428
1.00
23.07


ATOM
2100
CB
TYR
A
873
99.204
−91.450
89.464
1.00
23.56


ATOM
2101
CG
TYR
A
873
98.460
−92.330
88.485
1.00
23.45


ATOM
2102
CD1
TYR
A
873
98.474
−93.720
88.613
1.00
23.45


ATOM
2103
CD2
TYR
A
873
97.782
−91.778
87.401
1.00
23.36


ATOM
2104
CE1
TYR
A
873
97.828
−94.541
87.683
1.00
23.48


ATOM
2105
CE2
TYR
A
873
97.138
−92.584
86.467
1.00
23.37


ATOM
2106
CZ
TYR
A
873
97.160
−93.965
86.611
1.00
23.39


ATOM
2107
OH
TYR
A
873
96.493
−94.761
85.703
1.00
23.29


ATOM
2108
N
GLN
A
874
101.016
−91.727
86.752
1.00
22.91


ATOM
2109
CA
GLN
A
874
101.119
−91.372
85.336
1.00
22.59


ATOM
2110
C
GLN
A
874
100.367
−92.386
84.487
1.00
22.33


ATOM
2111
O
GLN
A
874
100.442
−93.587
84.741
1.00
22.29


ATOM
2112
CB
GLN
A
874
102.595
−91.324
84.901
1.00
22.63


ATOM
2113
CG
GLN
A
874
103.392
−90.216
85.582
1.00
22.75


ATOM
2114
CD
GLN
A
874
104.812
−90.065
85.047
1.00
22.81


ATOM
2115
OE1
GLN
A
874
105.567
−89.215
85.511
1.00
23.18


ATOM
2116
NE2
GLN
A
874
105.173
−90.882
84.073
1.00
22.92


ATOM
2117
N
MET
A
875
99.628
−91.911
83.486
1.00
21.97


ATOM
2118
CA
MET
A
875
98.910
−92.828
82.608
1.00
21.54


ATOM
2119
C
MET
A
875
99.911
−93.807
82.010
1.00
21.51


ATOM
2120
O
MET
A
875
101.098
−93.501
81.884
1.00
21.56


ATOM
2121
CB
MET
A
875
98.215
−92.081
81.466
1.00
21.00


ATOM
2122
CG
MET
A
875
96.949
−91.353
81.864
1.00
20.49


ATOM
2123
SD
MET
A
875
96.259
−90.504
80.454
1.00
19.48


ATOM
2124
CE
MET
A
875
97.185
−88.947
80.549
1.00
19.66


ATOM
2125
N
ALA
A
876
99.422
−94.981
81.637
1.00
21.51


ATOM
2126
CA
ALA
A
876
100.268
−95.998
81.043
1.00
21.53


ATOM
2127
C
ALA
A
876
100.574
−95.616
79.597
1.00
21.56


ATOM
2128
O
ALA
A
876
99.879
−94.787
78.999
1.00
21.38


ATOM
2129
CB
ALA
A
876
99.564
−97.357
81.097
1.00
21.51


ATOM
2130
N
GLN
A
877
101.632
−96.215
79.061
1.00
21.67


ATOM
2131
CA
GLN
A
877
102.064
−95.998
77.684
1.00
21.77


ATOM
2132
C
GLN
A
877
100.894
−96.234
76.716
1.00
21.95


ATOM
2133
O
GLN
A
877
100.245
−97.289
76.752
1.00
21.92


ATOM
2134
CB
GLN
A
877
103.208
−96.971
77.368
1.00
21.77


ATOM
2135
CG
GLN
A
877
103.813
−96.841
75.977
1.00
21.64


ATOM
2136
CD
GLN
A
877
104.932
−97.844
75.741
1.00
21.80


ATOM
2137
OE1
GLN
A
877
105.413
−98.497
76.675
1.00
21.64


ATOM
2138
NE2
GLN
A
877
105.356
−97.965
74.493
1.00
21.78


ATOM
2139
N
PRO
A
878
100.597
−95.252
75.850
1.00
22.05


ATOM
2140
CA
PRO
A
878
99.490
−95.449
74.913
1.00
22.13


ATOM
2141
C
PRO
A
878
99.821
−96.471
73.816
1.00
22.26


ATOM
2142
O
PRO
A
878
100.987
−96.702
73.484
1.00
22.07


ATOM
2143
CB
PRO
A
878
99.219
−94.037
74.396
1.00
22.08


ATOM
2144
CG
PRO
A
878
100.551
−93.384
74.473
1.00
22.05


ATOM
2145
CD
PRO
A
878
101.110
−93.871
75.782
1.00
22.09


ATOM
2146
N
ALA
A
879
98.775
−97.084
73.271
1.00
22.44


ATOM
2147
CA
ALA
A
879
98.910
−98.129
72.262
1.00
22.58


ATOM
2148
C
ALA
A
879
99.878
−97.899
71.102
1.00
22.73


ATOM
2149
O
ALA
A
879
100.713
−98.754
70.809
1.00
22.64


ATOM
2150
CB
ALA
A
879
97.530
−98.482
71.716
1.00
22.73


ATOM
2151
N
PHE
A
880
99.786
−96.745
70.453
1.00
22.85


ATOM
2152
CA
PHE
A
880
100.625
−96.488
69.294
1.00
22.98


ATOM
2153
C
PHE
A
880
101.909
−95.731
69.566
1.00
23.15


ATOM
2154
O
PHE
A
880
102.640
−95.379
68.641
1.00
23.15


ATOM
2155
CB
PHE
A
880
99.772
−95.791
68.235
1.00
23.04


ATOM
2156
CG
PHE
A
880
98.552
−96.588
67.857
1.00
23.09


ATOM
2157
CD1
PHE
A
880
98.646
−97.627
66.935
1.00
23.04


ATOM
2158
CD2
PHE
A
880
97.338
−96.376
68.508
1.00
23.14


ATOM
2159
CE1
PHE
A
880
97.552
−98.452
66.670
1.00
23.09


ATOM
2160
CE2
PHE
A
880
96.231
−97.196
68.256
1.00
23.12


ATOM
2161
CZ
PHE
A
880
96.340
−98.237
67.336
1.00
23.21


ATOM
2162
N
ALA
A
881
102.211
−95.517
70.840
1.00
23.27


ATOM
2163
CA
ALA
A
881
103.424
−94.798
71.192
1.00
23.53


ATOM
2164
C
ALA
A
881
104.637
−95.700
71.383
1.00
23.76


ATOM
2165
O
ALA
A
881
104.602
−96.664
72.156
1.00
23.69


ATOM
2166
CB
ALA
A
881
103.203
−93.978
72.459
1.00
23.52


ATOM
2167
N
PRO
A
882
105.720
−95.422
70.644
1.00
23.91


ATOM
2168
CA
PRO
A
882
106.904
−96.258
70.830
1.00
24.12


ATOM
2169
C
PRO
A
882
107.441
−95.835
72.198
1.00
24.22


ATOM
2170
O
PRO
A
882
107.054
−94.784
72.717
1.00
24.27


ATOM
2171
CB
PRO
A
882
107.821
−95.812
69.696
1.00
24.09


ATOM
2172
CG
PRO
A
882
106.855
−95.415
68.624
1.00
24.21


ATOM
2173
CD
PRO
A
882
105.821
−94.634
69.405
1.00
24.04


ATOM
2174
N
LYS
A
883
108.323
−96.641
72.776
1.00
24.33


ATOM
2175
CA
LYS
A
883
108.909
−96.336
74.071
1.00
24.37


ATOM
2176
C
LYS
A
883
109.508
−94.932
74.118
1.00
24.11


ATOM
2177
O
LYS
A
883
109.315
−94.204
75.088
1.00
24.06


ATOM
2178
CB
LYS
A
883
109.997
−97.369
74.398
1.00
24.87


ATOM
2179
CG
LYS
A
883
110.802
−97.090
75.661
1.00
25.38


ATOM
2180
CD
LYS
A
883
109.917
−97.062
76.904
1.00
25.81


ATOM
2181
CE
LYS
A
883
110.736
−97.159
78.197
1.00
26.11


ATOM
2182
NZ
LYS
A
883
111.720
−96.041
78.381
1.00
26.41


ATOM
2183
N
ASN
A
884
110.231
−94.548
73.071
1.00
23.79


ATOM
2184
CA
ASN
A
884
110.855
−93.231
73.055
1.00
23.47


ATOM
2185
C
ASN
A
884
109.859
−92.078
73.058
1.00
23.15


ATOM
2186
O
ASN
A
884
110.179
−90.992
73.543
1.00
23.21


ATOM
2187
CB
ASN
A
884
111.804
−93.091
71.859
1.00
23.61


ATOM
2188
CG
ASN
A
884
113.056
−93.933
72.009
1.00
23.79


ATOM
2189
OD1
ASN
A
884
113.320
−94.490
73.078
1.00
23.88


ATOM
2190
ND2
ASN
A
884
113.842
−94.025
70.938
1.00
23.72


ATOM
2191
N
ILE
A
885
108.658
−92.299
72.531
1.00
22.59


ATOM
2192
CA
ILE
A
885
107.653
−91.235
72.513
1.00
22.13


ATOM
2193
C
ILE
A
885
106.978
−91.171
73.889
1.00
21.79


ATOM
2194
O
ILE
A
885
106.548
−90.103
74.332
1.00
21.66


ATOM
2195
CB
ILE
A
885
106.603
−91.462
71.387
1.00
22.22


ATOM
2196
CG1
ILE
A
885
107.298
−91.425
70.016
1.00
22.22


ATOM
2197
CG2
ILE
A
885
105.512
−90.396
71.439
1.00
22.18


ATOM
2198
CD1
ILE
A
885
108.090
−90.146
69.753
1.00
22.35


ATOM
2199
N
TYR
A
886
106.919
−92.310
74.573
1.00
21.31


ATOM
2200
CA
TYR
A
886
106.331
−92.362
75.907
1.00
20.90


ATOM
2201
C
TYR
A
886
107.264
−91.631
76.872
1.00
20.71


ATOM
2202
O
TYR
A
886
106.811
−91.055
77.853
1.00
20.63


ATOM
2203
CB
TYR
A
886
106.130
−93.815
76.361
1.00
20.74


ATOM
2204
CG
TYR
A
886
105.467
−93.958
77.722
1.00
20.49


ATOM
2205
CD1
TYR
A
886
104.283
−93.273
78.023
1.00
20.44


ATOM
2206
CD2
TYR
A
886
106.019
−94.779
78.702
1.00
20.34


ATOM
2207
CE1
TYR
A
886
103.669
−93.404
79.269
1.00
20.32


ATOM
2208
CE2
TYR
A
886
105.414
−94.919
79.955
1.00
20.45


ATOM
2209
CZ
TYR
A
886
104.236
−94.230
80.231
1.00
20.40


ATOM
2210
OH
TYR
A
886
103.620
−94.386
81.457
1.00
20.39


ATOM
2211
N
SER
A
887
108.568
−91.658
76.583
1.00
20.36


ATOM
2212
CA
SER
A
887
109.555
−90.976
77.415
1.00
20.07


ATOM
2213
C
SER
A
887
109.370
−89.468
77.366
1.00
19.77


ATOM
2214
O
SER
A
887
109.770
−88.761
78.295
1.00
19.69


ATOM
2215
CB
SER
A
887
110.979
−91.313
76.970
1.00
20.21


ATOM
2216
OG
SER
A
887
111.309
−92.641
77.332
1.00
20.57


ATOM
2217
N
ILE
A
888
108.802
−88.970
76.270
1.00
19.33


ATOM
2218
CA
ILE
A
888
108.547
−87.536
76.159
1.00
18.95


ATOM
2219
C
ILE
A
888
107.416
−87.205
77.136
1.00
18.74


ATOM
2220
O
ILE
A
888
107.489
−86.220
77.875
1.00
18.70


ATOM
2221
CB
ILE
A
888
108.123
−87.139
74.724
1.00
18.86


ATOM
2222
CG1
ILE
A
888
109.254
−87.467
73.742
1.00
18.93


ATOM
2223
CG2
ILE
A
888
107.805
−85.635
74.658
1.00
18.93


ATOM
2224
CD1
ILE
A
888
108.882
−87.276
72.285
1.00
18.95


ATOM
2225
N
MET
A
889
106.373
−88.036
77.138
1.00
18.45


ATOM
2226
CA
MET
A
889
105.235
−87.836
78.032
1.00
18.23


ATOM
2227
C
MET
A
889
105.678
−87.844
79.496
1.00
18.15


ATOM
2228
O
MET
A
889
105.304
−86.968
80.276
1.00
18.09


ATOM
2229
CB
MET
A
889
104.188
−88.937
77.814
1.00
18.16


ATOM
2230
CG
MET
A
889
103.565
−88.931
76.434
1.00
18.13


ATOM
2231
SD
MET
A
889
102.506
−90.364
76.123
1.00
18.45


ATOM
2232
CE
MET
A
889
102.684
−90.510
74.362
1.00
18.11


ATOM
2233
N
GLN
A
890
106.475
−88.840
79.865
1.00
17.94


ATOM
2234
CA
GLN
A
890
106.962
−88.943
81.231
1.00
17.88


ATOM
2235
C
GLN
A
890
107.759
−87.700
81.616
1.00
17.71


ATOM
2236
O
GLN
A
890
107.658
−87.217
82.739
1.00
17.61


ATOM
2237
CB
GLN
A
890
107.830
−90.200
81.387
1.00
18.02


ATOM
2238
CG
GLN
A
890
107.055
−91.506
81.202
1.00
18.41


ATOM
2239
CD
GLN
A
890
107.954
−92.725
81.267
1.00
18.74


ATOM
2240
OE1
GLN
A
890
108.859
−92.887
80.444
1.00
19.12


ATOM
2241
NE2
GLN
A
890
107.718
−93.585
82.247
1.00
18.79


ATOM
2242
N
ALA
A
891
108.551
−87.189
80.680
1.00
17.69


ATOM
2243
CA
ALA
A
891
109.357
−85.993
80.930
1.00
17.67


ATOM
2244
C
ALA
A
891
108.456
−84.771
81.162
1.00
17.72


ATOM
2245
O
ALA
A
891
108.716
−83.953
82.050
1.00
17.75


ATOM
2246
CB
ALA
A
891
110.291
−85.738
79.755
1.00
17.60


ATOM
2247
N
CYS
A
892
107.407
−84.642
80.358
1.00
17.82


ATOM
2248
CA
CYS
A
892
106.471
−83.527
80.514
1.00
17.87


ATOM
2249
C
CYS
A
892
105.707
−83.666
81.841
1.00
17.96


ATOM
2250
O
CYS
A
892
105.198
−82.681
82.378
1.00
17.83


ATOM
2251
CB
CYS
A
892
105.451
−83.500
79.368
1.00
17.94


ATOM
2252
SG
CYS
A
892
106.091
−83.200
77.699
1.00
17.70


ATOM
2253
N
TRP
A
893
105.635
−84.887
82.363
1.00
18.05


ATOM
2254
CA
TRP
A
893
104.916
−85.132
83.602
1.00
18.21


ATOM
2255
C
TRP
A
893
105.788
−85.149
84.856
1.00
18.64


ATOM
2256
O
TRP
A
893
105.380
−85.667
85.895
1.00
18.66


ATOM
2257
CB
TRP
A
893
104.098
−86.432
83.494
1.00
17.81


ATOM
2258
CG
TRP
A
893
103.084
−86.416
82.359
1.00
17.21


ATOM
2259
CD1
TRP
A
893
102.465
−85.321
81.833
1.00
17.07


ATOM
2260
CD2
TRP
A
893
102.545
−87.552
81.660
1.00
16.95


ATOM
2261
NE1
TRP
A
893
101.577
−85.698
80.855
1.00
16.96


ATOM
2262
CE2
TRP
A
893
101.604
−87.061
80.729
1.00
16.89


ATOM
2263
CE3
TRP
A
893
102.764
−88.933
81.735
1.00
16.75


ATOM
2264
CZ2
TRP
A
893
100.877
−87.904
79.875
1.00
16.68


ATOM
2265
CZ3
TRP
A
893
102.043
−89.772
80.889
1.00
16.80


ATOM
2266
CH2
TRP
A
893
101.108
−89.250
79.969
1.00
16.69


ATOM
2267
N
ALA
A
894
106.982
−84.566
84.774
1.00
19.09


ATOM
2268
CA
ALA
A
894
107.847
−84.510
85.953
1.00
19.69


ATOM
2269
C
ALA
A
894
107.125
−83.661
86.995
1.00
20.05


ATOM
2270
O
ALA
A
894
106.596
−82.595
86.673
1.00
20.02


ATOM
2271
CB
ALA
A
894
109.189
−83.878
85.598
1.00
19.59


ATOM
2272
N
LEU
A
895
107.090
−84.126
88.240
1.00
20.71


ATOM
2273
CA
LEU
A
895
106.414
−83.369
89.290
1.00
21.27


ATOM
2274
C
LEU
A
895
107.086
−82.016
89.478
1.00
21.66


ATOM
2275
O
LEU
A
895
106.422
−81.001
89.664
1.00
21.82


ATOM
2276
CB
LEU
A
895
106.418
−84.157
90.605
1.00
21.38


ATOM
2277
CG
LEU
A
895
105.573
−85.433
90.596
1.00
21.51


ATOM
2278
CD1
LEU
A
895
105.815
−86.229
91.881
1.00
21.68


ATOM
2279
CD2
LEU
A
895
104.104
−85.065
90.451
1.00
21.66


ATOM
2280
N
GLU
A
896
108.411
−82.011
89.410
1.00
22.17


ATOM
2281
CA
GLU
A
896
109.192
−80.786
89.554
1.00
22.59


ATOM
2282
C
GLU
A
896
109.121
−80.066
88.203
1.00
22.53


ATOM
2283
O
GLU
A
896
109.698
−80.529
87.221
1.00
22.61


ATOM
2284
CB
GLU
A
896
110.640
−81.155
89.894
1.00
23.19


ATOM
2285
CG
GLU
A
896
111.499
−80.012
90.428
1.00
24.23


ATOM
2286
CD
GLU
A
896
110.932
−79.406
91.699
1.00
24.77


ATOM
2287
OE1
GLU
A
896
110.206
−78.393
91.611
1.00
24.96


ATOM
2288
OE2
GLU
A
896
111.206
−79.957
92.792
1.00
25.59


ATOM
2289
N
PRO
A
897
108.396
−78.932
88.133
1.00
22.41


ATOM
2290
CA
PRO
A
897
108.251
−78.161
86.894
1.00
22.32


ATOM
2291
C
PRO
A
897
109.571
−77.890
86.165
1.00
22.19


ATOM
2292
O
PRO
A
897
109.653
−78.070
84.951
1.00
22.05


ATOM
2293
CB
PRO
A
897
107.581
−76.874
87.366
1.00
22.31


ATOM
2294
CG
PRO
A
897
106.742
−77.344
88.505
1.00
22.28


ATOM
2295
CD
PRO
A
897
107.682
−78.271
89.240
1.00
22.41


ATOM
2296
N
THR
A
898
110.589
−77.455
86.911
1.00
22.12


ATOM
2297
CA
THR
A
898
111.896
−77.152
86.325
1.00
22.17


ATOM
2298
C
THR
A
898
112.592
−78.383
85.764
1.00
22.04


ATOM
2299
O
THR
A
898
113.626
−78.269
85.106
1.00
22.05


ATOM
2300
CB
THR
A
898
112.852
−76.485
87.348
1.00
22.19


ATOM
2301
OG1
THR
A
898
113.055
−77.365
88.462
1.00
22.26


ATOM
2302
CG2
THR
A
898
112.277
−75.159
87.832
1.00
22.30


ATOM
2303
N
HIS
A
899
112.042
−79.561
86.030
1.00
21.98


ATOM
2304
CA
HIS
A
899
112.637
−80.780
85.499
1.00
21.91


ATOM
2305
C
HIS
A
899
111.966
−81.201
84.193
1.00
21.60


ATOM
2306
O
HIS
A
899
112.332
−82.211
83.600
1.00
21.57


ATOM
2307
CB
HIS
A
899
112.559
−81.915
86.514
1.00
22.16


ATOM
2308
CG
HIS
A
899
113.549
−81.791
87.630
1.00
22.50


ATOM
2309
ND1
HIS
A
899
113.834
−82.830
88.489
1.00
22.74


ATOM
2310
CD2
HIS
A
899
114.313
−80.747
88.033
1.00
22.55


ATOM
2311
CE1
HIS
A
899
114.731
−82.430
89.375
1.00
22.82


ATOM
2312
NE2
HIS
A
899
115.037
−81.170
89.119
1.00
22.79


ATOM
2313
N
ARG
A
900
110.976
−80.428
83.755
1.00
21.20


ATOM
2314
CA
ARG
A
900
110.291
−80.727
82.502
1.00
20.91


ATOM
2315
C
ARG
A
900
111.087
−80.096
81.368
1.00
20.74


ATOM
2316
O
ARG
A
900
111.833
−79.141
81.582
1.00
20.75


ATOM
2317
CB
ARG
A
900
108.864
−80.161
82.509
1.00
20.57


ATOM
2318
CG
ARG
A
900
107.979
−80.787
83.564
1.00
20.04


ATOM
2319
CD
ARG
A
900
106.653
−80.064
83.717
1.00
19.75


ATOM
2320
NE
ARG
A
900
106.012
−80.458
84.965
1.00
19.42


ATOM
2321
CZ
ARG
A
900
105.119
−79.722
85.620
1.00
19.48


ATOM
2322
NH1
ARG
A
900
104.740
−78.538
85.145
1.00
19.31


ATOM
2323
NH2
ARG
A
900
104.641
−80.151
86.779
1.00
19.38


ATOM
2324
N
PRO
A
901
110.950
−80.629
80.148
1.00
20.66


ATOM
2325
CA
PRO
A
901
111.688
−80.057
79.022
1.00
20.84


ATOM
2326
C
PRO
A
901
111.013
−78.789
78.529
1.00
20.78


ATOM
2327
O
PRO
A
901
109.908
−78.447
78.963
1.00
20.66


ATOM
2328
CB
PRO
A
901
111.631
−81.167
77.978
1.00
20.82


ATOM
2329
CG
PRO
A
901
110.274
−81.767
78.231
1.00
20.83


ATOM
2330
CD
PRO
A
901
110.243
−81.858
79.744
1.00
20.69


ATOM
2331
N
THR
A
902
111.687
−78.089
77.630
1.00
20.78


ATOM
2332
CA
THR
A
902
111.138
−76.878
77.036
1.00
21.02


ATOM
2333
C
THR
A
902
110.505
−77.372
75.738
1.00
20.92


ATOM
2334
O
THR
A
902
110.794
−78.484
75.291
1.00
20.82


ATOM
2335
CB
THR
A
902
112.244
−75.855
76.695
1.00
21.04


ATOM
2336
OG1
THR
A
902
113.100
−76.405
75.689
1.00
21.30


ATOM
2337
CG2
THR
A
902
113.070
−75.531
77.922
1.00
21.03


ATOM
2338
N
PHE
A
903
109.633
−76.572
75.143
1.00
20.96


ATOM
2339
CA
PHE
A
903
108.998
−76.972
73.898
1.00
21.21


ATOM
2340
C
PHE
A
903
110.025
−77.083
72.779
1.00
21.58


ATOM
2341
O
PHE
A
903
109.899
−77.927
71.890
1.00
21.56


ATOM
2342
CB
PHE
A
903
107.903
−75.979
73.518
1.00
20.90


ATOM
2343
CG
PHE
A
903
106.636
−76.154
74.311
1.00
20.63


ATOM
2344
CD1
PHE
A
903
105.935
−77.358
74.263
1.00
20.55


ATOM
2345
CD2
PHE
A
903
106.142
−75.123
75.105
1.00
20.58


ATOM
2346
CE1
PHE
A
903
104.757
−77.531
74.993
1.00
20.42


ATOM
2347
CE2
PHE
A
903
104.967
−75.284
75.840
1.00
20.49


ATOM
2348
CZ
PHE
A
903
104.273
−76.491
75.783
1.00
20.45


ATOM
2349
N
GLN
A
904
111.038
−76.225
72.815
1.00
22.00


ATOM
2350
CA
GLN
A
904
112.075
−76.282
71.795
1.00
22.56


ATOM
2351
C
GLN
A
904
112.796
−77.621
71.899
1.00
22.63


ATOM
2352
O
GLN
A
904
113.086
−78.261
70.889
1.00
22.67


ATOM
2353
CB
GLN
A
904
113.067
−75.132
71.972
1.00
22.93


ATOM
2354
CG
GLN
A
904
114.103
−75.054
70.859
1.00
23.84


ATOM
2355
CD
GLN
A
904
113.474
−75.114
69.470
1.00
24.26


ATOM
2356
OE1
GLN
A
904
112.634
−74.278
69.110
1.00
24.68


ATOM
2357
NE2
GLN
A
904
113.879
−76.106
68.683
1.00
24.60


ATOM
2358
N
GLN
A
905
113.075
−78.053
73.124
1.00
22.82


ATOM
2359
CA
GLN
A
905
113.760
−79.321
73.335
1.00
22.99


ATOM
2360
C
GLN
A
905
112.903
−80.503
72.895
1.00
23.21


ATOM
2361
O
GLN
A
905
113.428
−81.512
72.424
1.00
23.11


ATOM
2362
CB
GLN
A
905
114.155
−79.471
74.798
1.00
23.04


ATOM
2363
CG
GLN
A
905
115.223
−78.484
75.232
1.00
23.19


ATOM
2364
CD
GLN
A
905
115.420
−78.484
76.730
1.00
23.22


ATOM
2365
OE1
GLN
A
905
114.542
−78.920
77.472
1.00
23.47


ATOM
2366
NE2
GLN
A
905
116.563
−77.973
77.186
1.00
23.20


ATOM
2367
N
ILE
A
906
111.587
−80.374
73.052
1.00
23.34


ATOM
2368
CA
ILE
A
906
110.667
−81.422
72.636
1.00
23.70


ATOM
2369
C
ILE
A
906
110.684
−81.479
71.106
1.00
24.23


ATOM
2370
O
ILE
A
906
110.596
−82.552
70.512
1.00
24.22


ATOM
2371
CB
ILE
A
906
109.214
−81.121
73.106
1.00
23.45


ATOM
2372
CG1
ILE
A
906
109.108
−81.256
74.629
1.00
23.27


ATOM
2373
CG2
ILE
A
906
108.236
−82.045
72.403
1.00
23.22


ATOM
2374
CD1
ILE
A
906
107.763
−80.801
75.198
1.00
22.92


ATOM
2375
N
CYS
A
907
110.783
−80.317
70.470
1.00
24.89


ATOM
2376
CA
CYS
A
907
110.808
−80.263
69.009
1.00
25.72


ATOM
2377
C
CYS
A
907
112.052
−80.975
68.478
1.00
26.30


ATOM
2378
O
CYS
A
907
111.976
−81.784
67.550
1.00
26.45


ATOM
2379
CB
CYS
A
907
110.813
−78.810
68.516
1.00
25.67


ATOM
2380
SG
CYS
A
907
109.247
−77.898
68.624
1.00
25.92


ATOM
2381
N
SER
A
908
113.199
−80.669
69.072
1.00
27.06


ATOM
2382
CA
SER
A
908
114.459
−81.268
68.653
1.00
27.82


ATOM
2383
C
SER
A
908
114.427
−82.791
68.707
1.00
28.26


ATOM
2384
O
SER
A
908
114.785
−83.455
67.737
1.00
28.18


ATOM
2385
CB
SER
A
908
115.603
−80.743
69.517
1.00
27.88


ATOM
2386
OG
SER
A
908
115.720
−79.339
69.375
1.00
28.33


ATOM
2387
N
PHE
A
909
113.998
−83.339
69.840
1.00
28.84


ATOM
2388
CA
PHE
A
909
113.926
−84.788
70.003
1.00
29.53


ATOM
2389
C
PHE
A
909
112.964
−85.399
68.987
1.00
30.09


ATOM
2390
O
PHE
A
909
113.268
−86.423
68.372
1.00
30.13


ATOM
2391
CB
PHE
A
909
113.472
−85.142
71.422
1.00
29.32


ATOM
2392
CG
PHE
A
909
113.515
−86.616
71.727
1.00
29.22


ATOM
2393
CD1
PHE
A
909
114.729
−87.297
71.773
1.00
29.15


ATOM
2394
CD2
PHE
A
909
112.341
−87.321
71.985
1.00
29.12


ATOM
2395
CE1
PHE
A
909
114.776
−88.654
72.073
1.00
29.07


ATOM
2396
CE2
PHE
A
909
112.377
−88.680
72.286
1.00
29.04


ATOM
2397
CZ
PHE
A
909
113.596
−89.348
72.330
1.00
29.07


ATOM
2398
N
LEU
A
910
111.803
−84.771
68.818
1.00
30.82


ATOM
2399
CA
LEU
A
910
110.804
−85.254
67.868
1.00
31.67


ATOM
2400
C
LEU
A
910
111.362
−85.247
66.452
1.00
32.45


ATOM
2401
O
LEU
A
910
110.975
−86.071
65.623
1.00
32.47


ATOM
2402
CB
LEU
A
910
109.542
−84.384
67.915
1.00
31.31


ATOM
2403
CG
LEU
A
910
108.583
−84.578
69.091
1.00
31.17


ATOM
2404
CD1
LEU
A
910
107.468
−83.541
69.002
1.00
30.98


ATOM
2405
CD2
LEU
A
910
108.006
−85.995
69.069
1.00
30.94


ATOM
2406
N
GLN
A
911
112.264
−84.309
66.181
1.00
33.43


ATOM
2407
CA
GLN
A
911
112.888
−84.192
64.865
1.00
34.52


ATOM
2408
C
GLN
A
911
113.793
−85.391
64.619
1.00
35.11


ATOM
2409
O
GLN
A
911
113.814
−85.947
63.524
1.00
35.18


ATOM
2410
CB
GLN
A
911
113.707
−82.906
64.783
1.00
34.80


ATOM
2411
CG
GLN
A
911
114.190
−82.557
63.380
1.00
35.39


ATOM
2412
CD
GLN
A
911
114.825
−81.171
63.311
1.00
35.71


ATOM
2413
OE1
GLN
A
911
115.114
−80.659
62.223
1.00
36.02


ATOM
2414
NE2
GLN
A
911
115.047
−80.559
64.473
1.00
35.86


ATOM
2415
N
GLU
A
912
114.524
−85.794
65.653
1.00
35.86


ATOM
2416
CA
GLU
A
912
115.428
−86.932
65.562
1.00
36.66


ATOM
2417
C
GLU
A
912
114.666
−88.250
65.423
1.00
37.15


ATOM
2418
O
GLU
A
912
115.113
−89.161
64.728
1.00
37.16


ATOM
2419
CB
GLU
A
912
116.330
−86.988
66.799
1.00
36.80


ATOM
2420
CG
GLU
A
912
116.947
−85.655
67.162
1.00
37.12


ATOM
2421
CD
GLU
A
912
117.928
−85.755
68.303
1.00
37.35


ATOM
2422
OE1
GLU
A
912
117.640
−86.487
69.273
1.00
37.59


ATOM
2423
OE2
GLU
A
912
118.987
−85.091
68.237
1.00
37.52


ATOM
2424
N
GLN
A
913
113.517
−88.357
66.084
1.00
37.74


ATOM
2425
CA
GLN
A
913
112.729
−89.584
66.009
1.00
38.42


ATOM
2426
C
GLN
A
913
112.096
−89.729
64.629
1.00
38.99


ATOM
2427
O
GLN
A
913
111.978
−90.834
64.102
1.00
39.02


ATOM
2428
CB
GLN
A
913
111.647
−89.594
67.099
1.00
38.29


ATOM
2429
CG
GLN
A
913
112.201
−89.568
68.523
1.00
38.16


ATOM
2430
CD
GLN
A
913
113.025
−90.800
68.869
1.00
38.15


ATOM
2431
OE1
GLN
A
913
112.494
−91.903
69.001
1.00
38.07


ATOM
2432
NE2
GLN
A
913
114.334
−90.614
69.017
1.00
38.13


ATOM
2433
N
ALA
A
914
111.701
−88.606
64.042
1.00
39.69


ATOM
2434
CA
ALA
A
914
111.097
−88.612
62.717
1.00
40.49


ATOM
2435
C
ALA
A
914
112.120
−89.030
61.661
1.00
41.07


ATOM
2436
O
ALA
A
914
111.808
−89.807
60.756
1.00
41.13


ATOM
2437
CB
ALA
A
914
110.547
−87.230
62.390
1.00
40.44


ATOM
2438
N
GLN
A
915
113.338
−88.511
61.777
1.00
41.81


ATOM
2439
CA
GLN
A
915
114.395
−88.838
60.825
1.00
42.59


ATOM
2440
C
GLN
A
915
114.746
−90.313
60.929
1.00
43.08


ATOM
2441
O
GLN
A
915
115.004
−90.975
59.922
1.00
43.10


ATOM
2442
CB
GLN
A
915
115.644
−87.995
61.092
1.00
42.69


ATOM
2443
CG
GLN
A
915
115.396
−86.498
61.101
1.00
42.98


ATOM
2444
CD
GLN
A
915
116.683
−85.691
61.083
1.00
43.23


ATOM
2445
OE1
GLN
A
915
116.707
−84.526
61.494
1.00
43.39


ATOM
2446
NE2
GLN
A
915
117.759
−86.302
60.592
1.00
43.27


ATOM
2447
N
GLU
A
916
114.754
−90.825
62.154
1.00
43.66


ATOM
2448
CA
GLU
A
916
115.062
−92.226
62.384
1.00
44.31


ATOM
2449
C
GLU
A
916
113.979
−93.091
61.747
1.00
44.73


ATOM
2450
O
GLU
A
916
114.256
−94.175
61.232
1.00
44.81


ATOM
2451
CB
GLU
A
916
115.142
−92.504
63.886
1.00
44.36


ATOM
2452
CG
GLU
A
916
115.302
−93.971
64.253
1.00
44.48


ATOM
2453
CD
GLU
A
916
116.492
−94.622
63.573
1.00
44.56


ATOM
2454
OE1
GLU
A
916
117.591
−94.026
63.586
1.00
44.55


ATOM
2455
OE2
GLU
A
916
116.326
−95.738
63.034
1.00
44.61


ATOM
2456
N
ASP
A
917
112.742
−92.603
61.779
1.00
45.22


ATOM
2457
CA
ASP
A
917
111.623
−93.339
61.204
1.00
45.71


ATOM
2458
C
ASP
A
917
111.718
−93.383
59.681
1.00
46.10


ATOM
2459
O
ASP
A
917
111.424
−94.407
59.064
1.00
46.11


ATOM
2460
CB
ASP
A
917
110.300
−92.697
61.618
1.00
45.71


ATOM
2461
CG
ASP
A
917
109.101
−93.403
61.020
1.00
45.71


ATOM
2462
OD1
ASP
A
917
108.907
−94.600
61.320
1.00
45.64


ATOM
2463
OD2
ASP
A
917
108.358
−92.760
60.247
1.00
45.74


ATOM
2464
N
ARG
A
918
112.124
−92.268
59.080
1.00
46.59


ATOM
2465
CA
ARG
A
918
112.259
−92.188
57.629
1.00
47.08


ATOM
2466
C
ARG
A
918
113.424
−93.037
57.130
1.00
47.31


ATOM
2467
O
ARG
A
918
113.389
−93.553
56.011
1.00
47.38


ATOM
2468
CB
ARG
A
918
112.455
−90.734
57.191
1.00
47.28


ATOM
2469
CG
ARG
A
918
111.186
−89.904
57.217
1.00
47.61


ATOM
2470
CD
ARG
A
918
111.465
−88.451
56.854
1.00
47.87


ATOM
2471
NE
ARG
A
918
112.334
−87.803
57.834
1.00
48.09


ATOM
2472
CZ
ARG
A
918
112.699
−86.527
57.781
1.00
48.15


ATOM
2473
NH1
ARG
A
918
113.492
−86.023
58.717
1.00
48.19


ATOM
2474
NH2
ARG
A
918
112.273
−85.754
56.790
1.00
48.24


ATOM
2475
N
ARG
A
919
114.456
−93.177
57.954
1.00
47.55


ATOM
2476
CA
ARG
A
919
115.612
−93.982
57.578
1.00
47.80


ATOM
2477
C
ARG
A
919
115.173
−95.378
57.155
1.00
47.84


ATOM
2478
O
ARG
A
919
115.439
−95.752
55.993
1.00
47.91


ATOM
2479
CB
ARG
A
919
116.590
−94.096
58.747
1.00
47.98


ATOM
2480
CG
ARG
A
919
117.532
−92.919
58.884
1.00
48.20


ATOM
2481
CD
ARG
A
919
118.492
−93.142
60.034
1.00
48.44


ATOM
2482
NE
ARG
A
919
119.059
−94.490
60.023
1.00
48.59


ATOM
2483
CZ
ARG
A
919
119.984
−94.915
60.878
1.00
48.65


ATOM
2484
NH1
ARG
A
919
120.447
−94.094
61.810
1.00
48.66


ATOM
2485
NH2
ARG
A
919
120.441
−96.158
60.804
1.00
48.62


ATOM
2486
OXT
ARG
A
919
114.564
−96.077
57.993
1.00
47.88


ATOM
2487
N1
LIG
B
1
87.953
−75.024
60.820
1.00
20.15


ATOM
2488
C2
LIG
B
1
87.885
−74.029
61.721
1.00
20.25


ATOM
2489
N3
LIG
B
1
88.796
−72.973
61.568
1.00
20.17


ATOM
2490
C4
LIG
B
1
88.772
−71.935
62.512
1.00
20.14


ATOM
2491
C5
LIG
B
1
87.819
−71.881
63.655
1.00
20.01


ATOM
2492
C6
LIG
B
1
86.950
−73.036
63.730
1.00
20.08


ATOM
2493
N7
LIG
B
1
86.947
−74.069
62.784
1.00
20.07


ATOM
2494
C8
LIG
B
1
87.735
−70.809
64.743
1.00
19.91


ATOM
2495
C9
LIG
B
1
89.001
−70.565
65.559
1.00
19.70


ATOM
2496
C10
LIG
B
1
89.665
−71.664
66.309
1.00
19.56


ATOM
2497
C11
LIG
B
1
90.897
−71.465
67.076
1.00
19.50


ATOM
2498
C12
LIG
B
1
91.477
−70.107
67.094
1.00
19.54


ATOM
2499
C13
LIG
B
1
90.816
−68.987
66.332
1.00
19.52


ATOM
2500
C14
LIG
B
1
89.580
−69.220
65.569
1.00
19.75


ATOM
2501
O15
LIG
B
1
92.664
−70.048
67.811
1.00
19.38


ATOM
2502
C16
LIG
B
1
93.340
−68.781
67.917
1.00
19.33


ATOM
2503
C17
LIG
B
1
94.338
−68.904
68.982
1.00
19.35


ATOM
2504
C18
LIG
B
1
95.768
−69.129
68.648
1.00
19.38


ATOM
2505
C19
LIG
B
1
96.766
−69.164
69.733
1.00
19.46


ATOM
2506
C20
LIG
B
1
96.337
−69.000
71.157
1.00
19.47


ATOM
2507
C21
LIG
B
1
94.883
−68.822
71.455
1.00
19.39


ATOM
2508
C22
LIG
B
1
93.893
−68.798
70.383
1.00
19.38


ATOM
2509
O23
LIG
B
1
97.383
−69.025
72.077
1.00
19.59


ATOM
2510
C24
LIG
B
1
97.118
−68.685
73.457
1.00
19.63


ATOM
2511
O25
LIG
B
1
91.607
−72.492
67.759
1.00
19.43


ATOM
2512
C26
LIG
B
1
91.023
−73.771
68.011
1.00
19.52


ATOM
2513
N27
LIG
B
1
89.728
−70.994
62.376
1.00
20.22


ATOM
2514
O
HOH
C
1
78.820
−73.654
77.373
1.00
19.24


ATOM
2515
O
HOH
C
2
91.210
−82.862
73.817
1.00
18.08


ATOM
2516
O
HOH
C
3
97.094
−84.418
84.144
1.00
17.67


ATOM
2517
O
HOH
C
4
99.687
−89.028
83.021
1.00
17.29


ATOM
2518
O
HOH
C
5
88.703
−83.415
74.883
1.00
17.82


ATOM
2519
O
HOH
C
6
93.701
−78.401
78.558
1.00
18.89


ATOM
2520
O
HOH
C
7
93.430
−71.398
88.869
1.00
25.82


ATOM
2521
O
HOH
C
8
89.183
−82.752
82.892
1.00
17.91


ATOM
2522
O
HOH
C
9
88.190
−83.098
62.548
1.00
22.13


ATOM
2523
O
HOH
C
10
101.769
−87.363
88.435
1.00
24.55


ATOM
2524
O
HOH
C
11
92.925
−71.283
78.765
1.00
20.63


ATOM
2525
O
HOH
C
12
97.542
−75.898
79.029
1.00
19.25


ATOM
2526
O
HOH
C
13
89.564
−93.244
69.962
1.00
19.39


ATOM
2527
O
HOH
C
14
95.267
−77.146
80.900
1.00
19.72


ATOM
2528
O
HOH
C
16
115.127
−59.707
82.667
1.00
26.66


ATOM
2529
O
HOH
C
17
88.724
−85.874
75.790
1.00
20.06


ATOM
2530
O
HOH
C
18
111.839
−89.182
79.925
1.00
24.03


ATOM
2531
O
HOH
C
19
74.485
−77.517
81.905
1.00
19.81


ATOM
2532
O
HOH
C
20
75.526
−77.434
74.151
1.00
22.32


ATOM
2533
O
HOH
C
21
104.311
−87.465
87.677
1.00
20.04


ATOM
2534
O
HOH
C
22
106.400
−88.766
88.822
1.00
28.97


ATOM
2535
O
HOH
C
23
111.159
−96.623
71.329
1.00
29.08


ATOM
2536
O
HOH
C
24
109.645
−59.975
81.044
1.00
22.04


ATOM
2537
O
HOH
C
25
92.057
−73.069
81.085
1.00
19.19


ATOM
2538
O
HOH
C
26
93.976
−74.326
83.136
1.00
25.74


ATOM
2539
O
HOH
C
27
109.275
−73.911
76.137
1.00
21.83


ATOM
2540
O
HOH
C
28
89.927
−67.909
69.279
1.00
22.86


ATOM
2541
O
HOH
C
29
90.752
−68.407
77.433
1.00
21.17


ATOM
2542
O
HOH
C
30
92.171
−74.817
55.187
1.00
25.32


ATOM
2543
O
HOH
C
31
88.720
−74.104
75.095
1.00
30.17


ATOM
2544
O
HOH
C
32
98.195
−76.828
84.252
1.00
31.02


ATOM
2545
O
HOH
C
33
107.829
−91.419
85.161
1.00
31.57


ATOM
2546
O
HOH
C
34
81.832
−77.650
82.629
1.00
29.52


ATOM
2547
O
HOH
C
35
99.032
−74.222
81.685
1.00
29.79


ATOM
2548
O
HOH
C
36
76.518
−76.360
83.555
1.00
31.49


ATOM
2549
O
HOH
C
37
115.252
−74.894
75.298
1.00
24.36


ATOM
2550
O
HOH
C
38
105.897
−69.850
61.080
1.00
34.95


ATOM
2551
O
HOH
C
39
71.283
−64.605
71.637
1.00
31.76


ATOM
2552
O
HOH
C
40
110.322
−71.301
72.626
1.00
24.81


ATOM
2553
O
HOH
C
41
104.302
−79.769
90.650
1.00
25.20


ATOM
2554
O
HOH
C
42
80.196
−59.912
68.541
1.00
25.49


ATOM
2555
O
HOH
C
43
87.943
−66.500
64.398
1.00
27.99


ATOM
2556
O
HOH
C
44
82.147
−77.364
65.927
1.00
25.90


ATOM
2557
O
HOH
C
45
78.891
−83.123
77.099
1.00
28.03


ATOM
2558
O
HOH
C
46
95.767
−83.158
85.978
1.00
23.90


ATOM
2559
O
HOH
C
47
104.844
−74.180
86.734
1.00
32.08


ATOM
2560
O
HOH
C
48
99.733
−70.306
58.451
1.00
23.83


ATOM
2561
O
HOH
C
49
104.245
−77.356
59.877
1.00
27.25


ATOM
2562
O
HOH
C
50
95.813
−65.894
66.634
1.00
24.21


ATOM
2563
O
HOH
C
51
111.093
−66.179
78.386
1.00
29.25


ATOM
2564
O
HOH
C
52
76.034
−61.107
76.239
1.00
44.40


ATOM
2565
O
HOH
C
53
105.325
−60.952
74.570
1.00
24.86


ATOM
2566
O
HOH
C
54
92.430
−70.004
90.824
1.00
42.70


ATOM
2567
O
HOH
C
55
90.502
−71.063
77.293
1.00
27.98


ATOM
2568
O
HOH
C
56
103.073
−98.089
80.718
1.00
19.56


ATOM
2569
O
HOH
C
57
110.972
−73.593
74.021
1.00
24.24


ATOM
2570
O
HOH
C
58
90.900
−87.316
74.421
1.00
17.46


ATOM
2571
O
HOH
C
59
105.194
−93.530
83.669
1.00
27.43


ATOM
2572
O
HOH
C
60
80.659
−83.692
78.565
1.00
29.19


ATOM
2573
O
HOH
C
61
87.066
−79.132
69.692
1.00
20.92


ATOM
2574
O
HOH
C
62
78.433
−78.956
72.588
1.00
37.79


ATOM
2575
O
HOH
C
63
84.753
−88.446
65.375
1.00
38.57


ATOM
2576
O
HOH
C
64
106.231
−81.734
60.864
1.00
36.73


ATOM
2577
O
HOH
C
65
75.494
−69.442
59.557
1.00
38.26


ATOM
2578
O
HOH
C
66
95.374
−72.520
56.932
1.00
32.84


ATOM
2579
O
HOH
C
67
98.574
−92.243
95.345
1.00
40.41


ATOM
2580
O
HOH
C
68
108.402
−86.651
89.048
1.00
37.14


ATOM
2581
O
HOH
C
69
94.944
−81.070
51.812
1.00
33.47


ATOM
2582
O
HOH
C
70
99.145
−60.402
81.632
1.00
45.72


ATOM
2583
O
HOH
C
71
98.020
−60.834
79.213
1.00
51.68


ATOM
2584
O
HOH
C
72
111.845
−71.353
70.232
1.00
48.86


ATOM
2585
O
HOH
C
73
109.611
−76.073
80.276
1.00
41.97


ATOM
2586
O
HOH
C
74
110.221
−84.279
89.188
1.00
33.27


ATOM
2587
O
HOH
C
75
107.372
−99.771
73.649
1.00
27.08


ATOM
2588
O
HOH
C
77
111.176
−95.743
68.722
1.00
35.72


ATOM
2589
O
HOH
C
78
110.354
−93.132
68.043
1.00
31.35


ATOM
2590
O
HOH
C
79
100.225
−99.680
77.985
1.00
22.42


ATOM
2591
O
HOH
C
80
103.380
−71.794
76.658
1.00
30.43


ATOM
2592
O
HOH
C
81
96.886
−68.134
88.963
1.00
44.12


ATOM
2593
O
HOH
C
82
108.757
−66.515
83.534
1.00
44.85


ATOM
2594
O
HOH
C
83
108.511
−57.676
81.951
1.00
31.79


ATOM
2595
O
HOH
C
84
109.663
−54.835
82.871
1.00
36.09


ATOM
2596
O
HOH
C
85
118.008
−64.497
76.818
1.00
45.87


ATOM
2597
O
HOH
C
86
113.000
−68.153
79.745
1.00
44.28


ATOM
2598
O
HOH
C
87
112.086
−61.307
73.799
1.00
28.84


ATOM
2599
O
HOH
C
88
109.480
−62.526
72.724
1.00
35.79


ATOM
2600
O
HOH
C
89
113.686
−62.398
80.305
1.00
33.64


ATOM
2601
O
HOH
C
90
107.287
−57.712
74.604
1.00
35.50


ATOM
2602
O
HOH
C
91
105.146
−58.297
75.578
1.00
35.93


ATOM
2603
O
HOH
C
92
101.656
−52.573
78.355
1.00
40.41


ATOM
2604
O
HOH
C
93
90.794
−50.511
72.030
1.00
47.23


ATOM
2605
O
HOH
C
94
91.548
−49.206
69.473
1.00
51.71


ATOM
2606
O
HOH
C
95
95.177
−48.246
66.523
1.00
36.93


ATOM
2607
O
HOH
C
96
96.500
−54.314
72.533
1.00
33.08


ATOM
2608
O
HOH
C
97
95.131
−55.501
68.416
1.00
27.23


ATOM
2609
O
HOH
C
98
96.469
−56.170
70.574
1.00
40.76


ATOM
2610
O
HOH
C
99
88.083
−50.728
67.931
1.00
34.77


ATOM
2611
O
HOH
C
100
93.405
−52.075
58.481
1.00
46.47


ATOM
2612
O
HOH
C
101
94.383
−56.688
58.741
1.00
50.76


ATOM
2613
O
HOH
C
102
79.900
−72.040
54.133
1.00
30.00


ATOM
2614
O
HOH
C
103
81.364
−76.289
68.114
1.00
27.22


ATOM
2615
O
HOH
C
104
75.303
−70.538
75.043
1.00
35.54


ATOM
2616
O
HOH
C
105
88.865
−66.057
67.079
1.00
27.43


ATOM
2617
O
HOH
C
106
77.619
−60.699
67.849
1.00
21.97


ATOM
2618
O
HOH
C
107
80.479
−57.883
70.502
1.00
33.14


ATOM
2619
O
HOH
C
108
77.184
−60.931
65.120
1.00
41.97


ATOM
2620
O
HOH
C
109
83.263
−57.212
71.749
1.00
31.99


ATOM
2621
O
HOH
C
110
100.861
−56.339
70.926
1.00
38.51


ATOM
2622
O
HOH
C
111
98.698
−55.770
69.139
1.00
36.72


ATOM
2623
O
HOH
C
112
97.835
−64.788
64.719
1.00
39.74


ATOM
2624
O
HOH
C
113
88.859
−64.544
69.263
1.00
27.71


ATOM
2625
O
HOH
C
114
105.882
−94.301
59.848
1.00
28.24


ATOM
2626
O
HOH
C
115
116.953
−82.093
66.009
1.00
36.17


ATOM
2627
O
HOH
C
116
109.710
−80.655
65.733
1.00
46.19


ATOM
2628
O
HOH
C
117
113.837
−72.757
74.801
1.00
32.06


ATOM
2629
O
HOH
C
118
115.166
−77.957
79.871
1.00
37.33


ATOM
2630
O
HOH
C
119
114.428
−75.677
81.136
1.00
45.18


ATOM
2631
O
HOH
C
120
111.060
−77.224
89.885
1.00
33.54


ATOM
2632
O
HOH
C
121
109.976
−74.871
90.692
1.00
39.60


ATOM
2633
O
HOH
C
122
105.708
−77.624
92.175
1.00
31.05


ATOM
2634
O
HOH
C
123
105.644
−74.721
91.291
1.00
40.28


ATOM
2635
O
HOH
C
124
102.815
−80.479
92.856
1.00
40.66


ATOM
2636
O
HOH
C
125
88.697
−84.103
58.822
1.00
30.65


ATOM
2637
O
HOH
C
126
90.415
−85.397
56.884
1.00
36.44


ATOM
2638
O
HOH
C
127
96.947
−84.499
53.567
1.00
34.18


ATOM
2639
O
HOH
C
128
91.899
−68.874
55.574
1.00
44.79


ATOM
2640
O
HOH
C
129
87.103
−93.604
68.048
1.00
32.28


ATOM
2641
O
HOH
C
130
103.631
−96.880
61.928
1.00
32.04


ATOM
2642
O
HOH
C
131
100.840
−96.600
64.145
1.00
44.14


ATOM
2643
O
HOH
C
132
100.694
−86.152
59.735
1.00
45.40


ATOM
2644
O
HOH
C
133
100.472
−83.398
59.470
1.00
40.35


ATOM
2645
O
HOH
C
134
98.032
−87.291
58.618
1.00
40.61


ATOM
2646
O
HOH
C
135
108.245
−68.079
78.043
1.00
35.34


ATOM
2647
O
HOH
C
136
86.462
−82.768
73.322
1.00
24.71


ATOM
2648
O
HOH
C
137
86.128
−81.698
75.616
1.00
29.61


ATOM
2649
O
HOH
C
138
92.379
−95.831
70.646
1.00
38.11


ATOM
2650
O
HOH
C
139
87.910
−92.262
72.101
1.00
31.36


ATOM
2651
O
HOH
C
140
88.170
−87.156
78.234
1.00
23.99


ATOM
2652
O
HOH
C
141
88.777
−93.633
76.636
1.00
26.56


ATOM
2653
O
HOH
C
142
94.995
−94.007
83.614
1.00
21.45


ATOM
2654
O
HOH
C
143
92.734
−95.597
83.791
1.00
26.22


ATOM
2655
O
HOH
C
144
88.907
−91.128
91.122
1.00
33.19


ATOM
2656
O
HOH
C
145
87.053
−93.455
89.140
1.00
35.14


ATOM
2657
O
HOH
C
146
79.694
−78.643
85.453
1.00
41.37


ATOM
2658
O
HOH
C
147
79.282
−79.540
82.363
1.00
43.66


ATOM
2659
O
HOH
C
148
86.267
−70.614
83.215
1.00
43.27


ATOM
2660
O
HOH
C
149
82.302
−79.158
87.974
1.00
36.44


ATOM
2661
O
HOH
C
150
87.429
−70.422
80.810
1.00
41.76


ATOM
2662
O
HOH
C
151
89.321
−73.406
80.701
1.00
28.86


ATOM
2663
O
HOH
C
152
95.403
−62.183
79.696
1.00
42.83


ATOM
2664
O
HOH
C
153
111.325
−64.602
85.894
1.00
44.96


ATOM
2665
O
HOH
C
154
107.804
−61.144
74.071
1.00
35.04


ATOM
2666
O
HOH
C
155
99.389
−54.262
72.384
1.00
47.89


ATOM
2667
O
HOH
C
156
97.587
−51.070
70.147
1.00
48.44


ATOM
2668
O
HOH
C
157
98.876
−55.986
66.495
1.00
34.72


ATOM
2669
O
HOH
C
158
93.523
−56.478
56.114
1.00
48.54


ATOM
2670
O
HOH
C
159
91.467
−54.818
54.293
1.00
46.12


ATOM
2671
O
HOH
C
160
83.992
−73.951
65.639
1.00
40.15


ATOM
2672
O
HOH
C
161
80.079
−76.994
70.717
1.00
30.00


ATOM
2673
O
HOH
C
162
83.191
−74.225
68.739
1.00
46.68


ATOM
2674
O
HOH
C
163
82.497
−76.889
72.311
1.00
25.98


ATOM
2675
O
HOH
C
164
83.446
−78.707
74.033
1.00
35.86


ATOM
2676
O
HOH
C
165
80.056
−79.909
74.373
1.00
39.56


ATOM
2677
O
HOH
C
166
86.743
−72.343
76.517
1.00
36.47


ATOM
2678
O
HOH
C
167
80.339
−82.333
75.077
1.00
41.28


ATOM
2679
O
HOH
C
168
87.010
−84.787
83.172
1.00
44.38


ATOM
2680
O
HOH
C
169
88.212
−88.605
80.498
1.00
47.00


ATOM
2681
O
HOH
C
170
100.640
−68.818
88.278
1.00
34.41


ATOM
2682
O
HOH
C
171
105.919
−73.455
88.943
1.00
28.12


ATOM
2683
O
HOH
C
172
106.350
−70.649
89.289
1.00
34.78


ATOM
2684
O
HOH
C
173
107.174
−68.153
84.755
1.00
29.49


ATOM
2685
O
HOH
C
174
108.020
−69.198
86.885
1.00
45.65


ATOM
2686
O
HOH
C
175
107.090
−70.063
82.584
1.00
35.05


ATOM
2687
O
HOH
C
176
89.839
−95.990
70.513
1.00
31.66


ATOM
2688
O
HOH
C
177
86.245
−96.029
68.213
1.00
39.26


ATOM
2689
O
HOH
C
178
85.197
−91.572
71.558
1.00
45.57


ATOM
2690
O
HOH
C
179
87.336
−89.700
96.243
1.00
45.40


ATOM
2691
O
HOH
C
180
102.077
−94.453
87.471
1.00
35.13


ATOM
2692
O
HOH
C
181
100.020
−96.719
84.747
1.00
47.89


ATOM
2693
O
HOH
C
182
105.473
−92.228
87.820
1.00
51.24


ATOM
2694
O
HOH
C
183
102.331
−100.426
79.359
1.00
33.37


ATOM
2695
O
HOH
C
184
104.620
−101.066
77.764
1.00
37.03


ATOM
2696
O
HOH
C
185
105.284
−98.924
68.539
1.00
43.33


ATOM
2697
O
HOH
C
186
107.945
−99.447
69.059
1.00
36.89


ATOM
2698
O
HOH
C
187
110.153
−97.990
67.782
1.00
40.97


ATOM
2699
O
HOH
C
188
112.537
−94.623
75.999
1.00
42.32


ATOM
2700
O
HOH
C
189
109.223
−94.650
78.613
1.00
39.46


ATOM
2701
O
HOH
C
190
108.658
−88.240
84.873
1.00
31.55


ATOM
2702
O
HOH
C
191
112.425
−85.594
87.586
1.00
54.08


ATOM
2703
O
HOH
C
192
117.159
−79.661
89.698
1.00
42.46


ATOM
2704
O
HOH
C
193
116.589
−77.662
71.428
1.00
40.35


ATOM
2705
O
HOH
C
194
116.739
−75.758
73.205
1.00
37.78


ATOM
2706
O
HOH
C
195
117.711
−89.479
64.063
1.00
41.29


ATOM
2707
O
HOH
C
196
111.481
−93.079
65.463
1.00
40.51


ATOM
2708
O
HOH
C
197
114.236
−95.689
67.751
1.00
41.02


ATOM
2709
O
HOH
C
198
108.489
−73.770
85.657
1.00
48.76


ATOM
2710
O
HOH
C
199
115.323
−96.534
70.607
1.00
51.48


ATOM
2711
O
HOH
C
200
107.669
−90.114
91.655
1.00
49.65


ATOM
2712
O
HOH
C
201
86.244
−95.303
80.834
1.00
48.45


ATOM
2713
O
HOH
C
202
87.199
−94.002
74.386
1.00
50.03


ATOM
2714
O
HOH
C
203
94.291
−64.806
81.761
1.00
40.32


ATOM
2715
O
HOH
C
204
93.056
−60.983
79.186
1.00
42.78


ATOM
2716
O
HOH
C
205
111.749
−59.184
72.239
1.00
43.92


ATOM
2717
O
HOH
C
206
100.244
−53.665
69.274
1.00
50.16


ATOM
2718
O
HOH
C
207
88.978
−46.187
67.628
1.00
43.97


ATOM
2719
O
HOH
C
208
89.165
−51.930
56.991
1.00
46.41


ATOM
2720
O
HOH
C
209
76.923
−64.275
74.150
1.00
44.26


ATOM
2721
O
HOH
C
210
83.188
−54.427
72.476
1.00
40.37


ATOM
2722
O
HOH
C
211
80.860
−53.610
71.161
1.00
39.81


ATOM
2723
O
HOH
C
212
105.365
−63.541
63.504
1.00
40.80


ATOM
2724
O
HOH
C
213
105.984
−62.164
65.900
1.00
41.33


ATOM
2725
O
HOH
C
214
108.031
−71.867
60.656
1.00
45.06


ATOM
2726
O
HOH
C
215
104.730
−68.665
58.732
1.00
48.93


ATOM
2727
O
HOH
C
216
118.493
−89.935
67.772
1.00
45.65


ATOM
2728
O
HOH
C
217
108.073
−84.824
62.444
1.00
41.90


ATOM
2729
O
HOH
C
218
115.472
−82.184
74.611
1.00
65.71


ATOM
2730
O
HOH
C
219
107.548
−80.478
93.056
1.00
48.08


ATOM
2731
O
HOH
C
220
106.570
−82.666
93.866
1.00
43.56


ATOM
2732
O
HOH
C
221
107.641
−90.970
87.806
1.00
43.09


ATOM
2733
O
HOH
C
222
113.394
−97.448
72.465
1.00
32.61


ATOM
2734
O
HOH
C
223
106.081
−92.234
91.740
1.00
40.74


ATOM
2735
O
HOH
C
224
103.608
−83.622
94.802
1.00
43.45


ATOM
2736
O
HOH
C
225
85.542
−77.303
58.419
1.00
38.63


ATOM
2737
O
HOH
C
226
85.801
−79.398
64.985
1.00
55.72


ATOM
2738
O
HOH
C
227
86.686
−82.171
69.803
1.00
42.56


ATOM
2739
O
HOH
C
228
83.126
−80.686
71.440
1.00
45.41


ATOM
2740
O
HOH
C
229
85.551
−85.887
69.448
1.00
44.24


ATOM
2741
O
HOH
C
230
84.479
−84.563
73.497
1.00
36.75


ATOM
2742
O
HOH
C
231
106.142
−97.152
61.057
1.00
47.55


ATOM
2743
O
HOH
C
232
108.447
−72.745
67.074
1.00
31.95


ATOM
2744
O
HOH
C
233
109.274
−70.180
67.814
1.00
43.76


ATOM
2745
O
HOH
C
234
109.118
−69.937
64.527
1.00
47.64


ATOM
2746
O
HOH
C
235
111.778
−69.345
74.102
1.00
35.18


ATOM
2747
O
HOH
C
236
88.662
−72.605
78.381
1.00
41.54


ATOM
2748
O
HOH
C
237
94.288
−68.038
89.654
1.00
46.35


ATOM
2749
O
HOH
C
238
83.710
−63.722
81.962
1.00
40.37


ATOM
2750
O
HOH
C
239
108.330
−67.803
80.449
1.00
37.00


ATOM
2751
O
HOH
C
240
119.325
−66.490
75.483
1.00
42.29


ATOM
2752
O
HOH
C
241
113.515
−63.136
72.433
1.00
43.49


ATOM
2753
O
HOH
C
242
109.594
−59.379
73.468
1.00
39.75


ATOM
2754
O
HOH
C
243
90.951
−55.822
76.333
1.00
44.26


ATOM
2755
O
HOH
C
244
87.061
−50.366
58.145
1.00
43.01


ATOM
2756
O
HOH
C
245
84.786
−60.046
51.622
1.00
33.53


ATOM
2757
O
HOH
C
246
80.488
−77.016
59.865
1.00
29.43


ATOM
2758
O
HOH
C
247
76.165
−56.649
81.565
1.00
38.01


ATOM
2759
O
HOH
C
248
85.163
−52.841
70.845
1.00
37.13


ATOM
2760
O
HOH
C
249
81.016
−53.253
68.420
1.00
42.06


ATOM
2761
O
HOH
C
250
79.222
−55.726
70.403
1.00
39.42


ATOM
2762
O
HOH
C
251
103.336
−61.264
63.121
1.00
37.27


ATOM
2763
O
HOH
C
252
106.162
−65.055
60.097
1.00
41.20


ATOM
2764
O
HOH
C
253
106.400
−67.250
62.639
1.00
37.38


ATOM
2765
O
HOH
C
254
100.113
−73.798
57.938
1.00
37.83


ATOM
2766
O
HOH
C
255
108.871
−72.425
63.401
1.00
44.07


ATOM
2767
O
HOH
C
256
90.412
−73.463
52.583
1.00
39.94


ATOM
2768
O
HOH
C
257
84.800
−91.037
65.780
1.00
44.81


ATOM
2769
O
HOH
C
258
94.924
−94.470
62.475
1.00
34.35


ATOM
2770
O
HOH
C
259
97.369
−95.560
64.039
1.00
40.90


ATOM
2771
O
HOH
C
260
109.696
−65.795
68.485
1.00
37.06


ATOM
2772
O
HOH
C
261
110.693
−68.163
76.371
1.00
41.43


ATOM
2773
O
HOH
C
262
98.419
−72.575
56.636
1.00
39.73


ATOM
2774
O
HOH
C
263
93.806
−67.354
55.165
1.00
37.51


ATOM
2775
O
HOH
C
264
118.300
−87.590
71.950
1.00
40.52


ATOM
2776
O
HOH
C
265
112.255
−76.653
82.170
1.00
33.98


ATOM
2777
O
HOH
C
266
102.339
−99.592
68.160
1.00
42.20


ATOM
2778
O
HOH
C
267
100.139
−92.592
92.839
1.00
41.71


ATOM
2779
O
HOH
C
268
85.770
−86.081
75.298
1.00
43.00


ATOM
2780
O
HOH
C
269
100.537
−72.051
81.519
1.00
39.66


ATOM
2781
O
HOH
C
270
87.364
−80.829
91.647
1.00
33.99


ATOM
2782
O
HOH
C
271
91.802
−68.909
88.818
1.00
42.25


ATOM
2783
O
HOH
C
272
94.063
−68.824
87.400
1.00
44.78


ATOM
2784
O
HOH
C
273
87.264
−64.128
49.727
1.00
41.75


ATOM
2785
O
HOH
C
274
84.187
−75.560
70.350
1.00
22.00


ATOM
2786
O
HOH
C
275
95.221
−73.133
96.184
1.00
31.75


ATOM
2787
O
HOH
C
276
91.373
−72.038
93.361
1.00
35.12


END









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## Claims

1. A compound selected from the group consisting of:




salts thereof.

2. The compound of claim 1 or salt thereof, wherein said compound has Formula (Id):

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1, or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 2, or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.