# Patent

## Title
Method of treating HCV infection with a small molecule CHK2 inhibitor

## Abstract

A method of treating an Hepatitis C Virus infection in a patient, comprising providing a therapeutically effective amount, to a patient in need thereof, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: G1 is a group of the formula or where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S, which Het is optionally substituted.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Stage of International Patent Application No. PCT/US2012/062212 filed Oct. 26, 2012, which claims the benefit of U.S. Provisional Application No. 61/551,742, filed 26 Oct. 2011, both of which are incorporated herein by reference in their entirety.


STATEMENT OF GOVERNMENT INTEREST
Research supporting this disclosure was performed in part with support from United States of America as represented by the Secretary of the Department of Health and Human Services. The federal government has certain rights in this disclosure.


FIELD OF THE DISCLOSURE
The present disclosure provides a method of treating an HCV (Hepatitis C Virus) infection in a patient comprising administering a therapeutically effective amount of a Chk2 (Checkpoint kinase 2) inhibitor to a patient infected with an HCV virus. In certain embodiments, the Chk2 inhibitor is a hydrazine-carbamimide containing compound of Formula I (shown below). The Chk2 inhibitor may be the only active agent or may be administered together with one or more additional active agents that are not CHk2 inhibitors. The disclosure also provides methods of inhibiting HCV replication in vitro and in vivo by contacting HCV infected cells with a Chk2 inhibitor.
BACKGROUND
An estimated 3% of the world's population is infected with the hepatitis C virus. Of those exposed to HCV, 80% to 85% become chronically infected, at least 30% develop cirrhosis of the liver, and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will spontaneously clear HCV.
HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.
The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is: NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.
The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.
Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. U.S. Provisional Application No. 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.
Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient's adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as BI 201335 (Boehringer Ingelheim), TMC435 (Tibotec), Telaprevir (Vertex), and Boceprevir (Merck) may be used for treatment of chronic HCV. Each of these drugs, may be used in combination with an immune modulator, such as interferon, or an additional anti-viral agent. Due to the high mutation rate of HCV and dearth of effective HCV therapeutics, new therapies are needed. Compounds that inhibit HCV replication via a different mechanism than those currently employed are particularly desirable.
HCV infection and the expression of the HCV non-structural protein NS3 has been proposed as a cause of double-stranded DNA breaks, possibly leading to the enhanced mutation rate of cellular genes in HCV-infected cells. DNA damage sensors, such as ataxia-telangiectasia mutated kinase (ATM), ATM- and Rad3-related kinase (ATR), poly(ADP-ribose) polymerase 1 (PARP-1) and checkpoint kinase 2 (Chk2) play central roles in the response to genotoxic stress. Ariumi, et al. determined that replication of genome-length HCV RNA and subgenomic HCV replicon RNA was suppressed in ATM- and Chk2-knockdown cells. (J. Virology, (2008) 82(19): 9639-9646). Ariumi identified the ATM-signaling pathway as a possible target for novel therapeutics useful for treating chronic HCV infection.
The present disclosure fulfills the need for HCV replication inhibitors that act via a novel mechanism, in this case Chk2 inhibition, and provides additional advantages, which are described herein.
SUMMARY
Chk2 inhibitors useful as HCV replication inhibitors are provided herein. The compounds of Formula I provided in this disclosure possess antiviral activity.
The disclosure provides certain novel compounds of Formula I, useful as Chk2 inhibitors. In a one aspect the disclosure provides a method of treating a hepatitis C (HCV) infection in a patient, comprising providing a therapeutically effective amount, to a patient in need thereof, of a Chk2 inhibitor. The disclosure also provides a method of inhibiting replication of a Hepatitis C Virus comprising contacting the virus, in vivo or in vitro with a concentration a Chk2 inhibitor sufficient to inhibit Hepatitis C Virus replication in vitro. The Chk2 inhibitor may be compound of Formula I




or a pharmaceutically acceptable salt thereof.

Within Formula I the variables Ar1, R, Ar2, and G1 carry the following definitions.
G1 is a group of the formula




where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted.

Ar1 is a 6,6-fused or 6,5 bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which Ar1 is optionally substituted.
Ar2 is phenyl, a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, or a 6,5 bicyclic aromatic ring system containing 1, 2, or 3 nitrogen atoms, with remaining atoms being carbon, which Ar2 is optionally substituted.
R is a group of the formula —NH(C═O)— or —(O═C)NH—; R3 is hydrogen or C1-C6alkyl.
R3 is taken together with an Ar2 substituent to form a 5- or 6-membered unsaturated or aromatic R3/Ar2 ring having 0, 1, or 2 heteroatoms independently chosen from N, O, and S, which R3/Ar2 ring is optionally substituted.
R4 is hydrogen or C1-C6alkyl.
R5 is amino, —NHOH, or optionally substituted mono- or di-alkylamino, and R6 is hydrogen or hydroxyl; or R5 and R6 are taken together to form a 5 or 6-membered heterocyclic ring, which is unsaturated or aromatic and which contains 0, 1 or 2 additional heteroatoms chosen from N, S, and O, which 5 or 6-membered heterocyclic ring is optionally substituted.
Within Formula I the variables Ar1, Ar2, R3, and R4 carry the following definitions.
Ar1 is a 6,6-fused bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which Ar1 is optionally substituted.
Ar2 is phenyl or a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, which Ar2 is optionally substituted.
R3 is hydrogen or C1-C6alkyl.
R4 is hydroxyl or amino.
The disclosure also provides a method of inhibiting replication of an HCV, in vivo or in vitro, comprising contacting HCV infected cells with a therapeutically effective amount of a compound of Formula I.
In either of the preceding methods the compound or salt of Formula I may be administered as the only active agent or together with a therapeutically effective amount of at least one additional active agent. The additional active agent can be another compound of Formula I or an active agent that is not a compound of Formula I such as an interferon or non-Chk2 directed anti-HCV agent.
The disclosure provides compounds of Formula I that are potent and/or selective inhibitors of Hepatitis C virus replication. Without being bound to any particular theory it is believed the present compounds are potent and selective inhibitors of Chk2 Pharmaceutical compositions containing one or more compounds or salts of Formula I, together with pharmaceutically acceptable carriers are also provided herein.
Certain compounds of Formula I disclosed herein exhibit good activity in an HCV replication assay, such as the HCV replicon assay set forth in Example 2, which follows. Preferred compounds of Formula I exhibit an EC50 of about 10 micromolar or less, or more preferably an EC50 of about 1.5 micromolar or less. Preferred compounds Chk2 inhibitors that inhibit HCV replication exhibit a cytotoxicity IC50 of greater than 10 micromolar in a standard assay of cytotoxicity such as the assay of Example 3, which follows. Preferred Chk2 inhibitor/anti-HCV compounds also exhibit IC50/EC50 (Selectivity ratio) of 4 or greater.



BRIEF DESCRIPTION OF THE DRAWINGS
The present patent application contains at least one drawing executed in color. Copies of this application with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
FIG. 1 shows the structure of the HCV Replicon from the Huh7 ET cell line. The HCV RNA replicon ET contains the 5′ NTR (IRES) of HCV (5′) which drives the production of a firefly luciferase (Luc), ubiquitin (Ubiq), and neomycin phosphotransferase (Neo) fusion protein. Ubiquitin cleavage releases the LUC and Neo genes. The EMCV IRES element (E-I) controls the translation of the HCV structural proteins NS3-NS5. The NS3 protein cleaves the HCV polyprotein to release the mature NS3, NS4A, NS4B, NS5A, and NS5B proteins that are required for HCV replication. At the 3′ end of the replicon is the authentic 3′ NTR of HCV.
FIG. 2 shows the effect of increasing concentrations of Compound 14 on HCV replication and cell viability.
FIG. 3 shows the effect of increasing concentrations of Compound 10 on HCV replication and cell viability.
FIG. 4 shows co-crystal structure of Compound 14 (PV-1549) in the catalytic domain of the CHK2 kinase.



DETAILED DESCRIPTION
Chemical Description and Terminology
Prior to setting forth the invention in detail, it may be helpful to provide definitions of certain terms to be used in this disclosure. Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. Unless clearly contraindicated by the context each compound name includes the free acid or free base form of the compound as well as all pharmaceutically acceptable salts of the compound.
The term “compounds of Formula I” encompasses all compounds that satisfy Formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of such compounds. The phrase “a compound of Formula I” includes all subgeneric groups of Formula I, including compounds of Formula IA, IB, and IC, and also includes pharmaceutically acceptable salts of a compound of Formula I, unless clearly contraindicated by the context in which this phrase is used.
The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or.” The open-ended transitional phrase “comprising” encompasses the intermediate transitional phrase “consisting essentially of” and the close-ended phrase “consisting of” Claims reciting one of these three transitional phrases, or with an alternate transitional phrase such as “containing” or “including” can be written with any other transitional phrase unless clearly precluded by the context or art. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
An “active agent” means a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient. The indirect physiological effect may occur via a metabolite or other indirect mechanism.
A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —(C═O)OH is attached through carbon of the keto (C═O) group.
“Alkanoyl” is an alkyl group as defined herein, covalently bound to the group it substitutes by a keto (—(C═O)—) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2alkanoyl group is an acetyl group having the formula CH3(C═O)—.
“Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms. The term C1-C6alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. C1-C8alkyl, C1-C4alkyl, and C1-C2alkyl. When C0-Cn, alkyl is used herein in conjunction with another group, for example, (mono- or di-C1-C4alkylamino)C0-C4 alkyl, the indicated group, in this case alkylamino, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.
“Alkoxy” is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
“Haloalkyl” includes both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
“Haloalkoxy” is a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
“Halo” or “halogen” indicates any of fluoro, chloro, bromo, and iodo.
“Mono- and/or di-alkylamino” is a secondary or tertiary alkyl amino group, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. In some instances the mono- and/or di-alkyl amino group is attached to the group it substitutes via a C0-C4alkyl linker “Optionally substituted mono- and/or di-alkylamino” includes mono- and di-alkylamino groups as described in this paragraph, optionally substituted with the substituents chosen from the group of optional substituents listed in this section. In certain embodiments the “optionally substituted mono- and/or di-alkylamino” optionally contains one or more double or triple bonds in its alkyl groups, and is optionally substituted one or more substituents independently chosen from halogen, hydroxyl, amino, oxo, C1-C4 alkoxy, C1-C4alkylamino, and C3-C7cycloalkyl.
The term “substituted” means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., ═O) then 2 hydrogens on the atom are replaced. When an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent. Unless otherwise specified substituents are named into the core structure. For example, it is to be understood that when aminoalkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.
Groups that may be present on a “substituted” or “optionally substituted” position include, but are not limited to, e.g., halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl groups (including cycloalkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms.
In certain embodiments, an “optionally substituted” group is substituted with one or more substituents independently selected from halogen, hydroxyl, amino, nitro, cyano, oxo, —NHOH, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C2-C6alkylester, C3-C7cycloalkyl, phenyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, which may be optionally substituted, C1-C2haloalkyl, and C1-C2haloalkoxy.
A “dosage form” means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
“Pharmaceutical compositions” are compositions comprising at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier. Pharmaceutical compositions optional contain one or more additional active agents. When specified, pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs.
“Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n—COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).
The term “carrier” applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided. To be pharmaceutically acceptable a carrier must be safe, non-toxic and neither biologically nor otherwise undesirable.
A “patient” is a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In certain embodiments disclosed herein, “medical treatment” means treatment of existing acute or chronic HCV infections. In certain embodiments, the patient is a human patient.
“Provided together with at least one additional active agent” means the Chk2 inhibitor and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the Chk2 inhibitor and the at least one additional active agent are within the blood stream of a patient. In certain embodiments, the Chk2 inhibitor and the additional active agent need not be prescribed for a patient by the same medical care worker. In certain embodiments, the additional active agent or agents need not require a prescription. Administration of the Chk2 inhibitor or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories or topical contact.
“Treatment” as used herein includes providing a compound of Formula I, either as the only active agent or together with at least one additional active agent sufficient to: (a) prevent a disease or a symptom of a disease from occurring in a patient who may be predisposed to the disease but has not yet been diagnosed as having it (e.g. including diseases that may be associated with or caused by a primary disease (as in liver fibrosis that can result in the context of chronic HCV infection); (b) inhibiting the disease, i.e. arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. “Treating” and “treatment” also means providing a therapeutically effective amount of a Chk2 inhibitor as the only active agent or together with at least one additional active agent to a patient having or susceptible to a hepatitis C infection.
A “therapeutically effective amount” of a pharmaceutical composition/combination means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a HCV infection. For example, a patient infected with HCV may present elevated levels of certain liver enzymes, including AST and ALT. Normal levels of AST are from 5 to 40 units per liter of serum (the liquid part of the blood) and normal levels of ALT are from 7 to 56 units per liter of serum. A therapeutically effect amount is thus an amount sufficient to provide a significant reduction in elevated AST and ALT levels or an amount sufficient to provide a return of AST and ALT levels to the normal range. A therapeutically effective amount is also an amount sufficient to prevent a significant increase or significantly reduce the detectable level of virus or viral antibodies in the patient's blood, serum, or tissues. One method of determining treatment efficacy includes measuring HCV RNA levels by a conventional method for determining viral RNA levels such as the Roche TaqMan assay. In certain preferred embodiments treatment reduces HCV RNA levels below the limit of quantitation (30 IU/mL, as measured by the Roche TaqMan® assay) or more preferably below the limit of detection (10 IU/mL, Roche TaqMan).
A significant increase or reduction in the detectable level of virus or viral antibodies is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p<0.05.
Chemical Description
The disclosure provides a method of treating HCV infection in a patient, comprising administering a therapeutically effective amount of a Chk2 inhibitor to a patient in need of such treatment. Chk2 inhibitors have been disclosed previously. Chk2 inhibitors particularly useful for treating HCV include compounds disclosed in U.S. application Ser. No. 11/989,737 filed 3 Sep. 2009, which is hereby incorporated by reference at pages 12-14 for its disclosure of particular Chk2 inhibitor compounds and at pages 2-5 for its disclosure of a class of Chk2 inhibitor compounds. Chk2 inhibitors have also been disclosed in US 2009/0018141 (Ser. No. 13/557,508) filed 9 Jun. 2009, which is hereby incorporated by reference at paragraphs [0008]-[0009], [0054]-[0133], and [0135]-[0209] for its general description of Chk2 inhibitors and at paragraph [0210] (TABLE I) for its disclosure of specific Chk2 inhibitors.
Formula I includes all subformulae thereof. In certain situations, the compounds of Formula I may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example using a chiral HPLC column.
Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.
The present disclosure includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C.
The Chk2 inhibitors disclosed herein as useful for treating HCV infection include compounds and salts of Formula I, where




wherein in Formula I, G1 is a group of the formula





and the variables Ar1, Ar3, and R carry the definitions set forth in the “SUMMARY” section. Alternatively the variables carry any of the definitions set forth below. Any combination of the variables that results in a stable compound is within the scope of the disclosure.

(1) R is —NH(C═O)—.
(2) R is —(C═O)NH—.
(3) G1 is a group of the formula




(4) G1 is a group of the formula




where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted.

(4) G1 is a group of the formula




where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted with amino, —NHOH, or optionally substituted (mono- or di-C1-C6alkylamino)C0-C4alkyl.

(5) Het is a basic heteroaryl group or Het is a heteroaryl group that is substituted with a basic amino substituent such as an amino, NHOH, or optionally substituted mono- or di-C1-C6alkylamino)C0-C4alkyl.
(6) G1 carries the definition set forth in (4) except n is 0 or 1 and Het is an optionally substituted imidazolyl group. In certain embodiments, the imidazolyl group is substituted with 0 to 2 substituents independently chosen from halogen, hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, and (mono- and di-C1-C4alkylamino)C0-C2alkyl.
(7) Ar1 and Ar1 are independently chosen from quinolinyl, isoquinolinyl, benzimidazolyl, indolyl, naphthyl, phenyl, pyridyl, and pyrimidinyl groups, wherein:
(i) Ar1 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C3-C7cycloalkyl, 5- to 7-membered heterocycloalkyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; and
(ii) Ar2 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, C1-C4alkyl, C1-C4alkoxy, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.
(8) A1 is chosen from quinolinyl, isoquinolinyl, benzimidazolyl, indolyl, naphthyl, phenyl, pyridyl, and pyrimidinyl groups, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C3-C7cycloalkyl, 5- to 7-membered heterocycloalkyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; and Ar2 is imidazolyl, which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, amino, C1-C2alkyl, C1-C2alkoxy, (mono- or di-C1-C2alkylamino)C0-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.
(9) The compound is a compound of Formula IA-IC.




(10) Included herein are compounds of Formula I and IA-IC in which:
R1 is absent or is 1 or more substituents bound to either ring of the bicyclic system and independently selected from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C3-C7cycloalkyl, 5- to 7-membered heterocycloalkyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R2 is absent or is 1 or more substituents independently selected from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.
(11) R3 is methyl, R5 is amino, and R6 is hydrogen.
(12) R1 is 1 or 2 substituents independently chosen from halogen, nitro, acetyl, C1-C2alkyl, and C1-C2alkoxy.
(13) R2 is absent.
The following compounds and their pharmaceutically acceptable salts shown and described in Examples 1-15 are also included in this disclosure.
Pharmaceutical Preparations
Compounds disclosed herein can be administered as the neat chemical, but are preferably administered as a pharmaceutical composition. Accordingly, the disclosure provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of a Chk2 inhibitor, such as a compound of Formula I, together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition/combination may contain a compound or salt of Formula I as the only active agent, but is preferably contains at least one additional active agent. In certain embodiments it is preferred that the additional active agent is an NS3 protease inhibitor. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of a compound of Formula I and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. The pharmaceutical composition may also include a molar ratio of a compound of Chk2 inhibitor, such as a compound of Formula I, and an additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an NS3 protease inhibitor of Formula II to NS5a inhibitor of Formula I.
Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
The pharmaceutical compositions/combinations can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt. %) of a compound of Formula I and usually at least about 5 wt. % of a compound of Formula. Some embodiments contain from about 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the compound of Formula.
Methods of Treatment
The pharmaceutical compositions/combinations disclosed herein are useful for treating hepatitis C infections in patients.
This disclosure provides methods of treating viral infections, including hepatitis C infections, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to patient infected with a hepatitis C virus. A compound or salt of Formula I may be provided as the only active agent or may be provided together with one or more additional active agents. In certain embodiments, the Chk2 kinase inhibitor is administered together with interferon, a Hepatitis C Virus NS3 inhibitor, Hepatitis C Virus protease inhibitor, Hepatitis C Virus NS4a inhibitor, or a Hepatitis C Virus NS5a inhibitor, or other anti-Hepatitis C Virus compound.
In certain embodiments, the other anti-Hepatitis C Virus compound is not a Chk2 kinase inhibitor and/or is not a compound or salt of Formula I.
An effective amount of a pharmaceutical composition/combination of the invention may be an amount sufficient to (a) inhibit the progression of hepatitis C; (b) cause a regression of the hepatitis C infection; or (c) cause a cure of a hepatitis C infection such that HCV virus or HCV antibodies can no longer be detected in a previously infected patient's blood or plasma. An amount of a pharmaceutical composition/combination effective to inhibit the progress or cause a regression of hepatitis C includes an amount effective to stop the worsening of symptoms of hepatitis C or reduce the symptoms experienced by a patient infected with the hepatitis C virus. Alternatively, a halt in progression or regression of hepatitis C may be indicated by any of several markers for the disease. For example, a lack of increase or reduction in the hepatitis C viral load or a lack of increase or reduction in the number of circulating HCV antibodies in a patient's blood are markers of a halt in progression or regression of hepatitis C infection. Other hepatitis C disease markers include aminotransferase levels, particularly levels of the liver enzymes AST and ALT. Normal levels of AST are from 5 to 40 units per liter of serum (the liquid part of the blood) and normal levels of ALT are from 7 to 56 units per liter of serum. These levels will typically be elevated in a HCV infected patient. Disease regression is usually marked by the return of AST and ALT levels to the normal range.
Symptoms of hepatitis C that may be affected by an effective amount of a pharmaceutical composition/combination of the invention include decreased liver function, fatigue, flu-like symptoms: fever, chills, muscle aches, joint pain, and headaches, nausea, aversion to certain foods, unexplained weight loss, psychological disorders including depression, tenderness in the abdomen, and jaundice.
“Liver function” refers to a normal function of the liver, including, but not limited to, a synthetic function including synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5′-nucleosidase, y glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; and a hemodynamic function, including splanchnic and portal hemodynamics.
An effective amount of a pharmaceutical composition/combination described herein will also provide a sufficient concentration of the active agents in the concentration when administered to a patient. A sufficient concentration of an active agent is a concentration of the agent in the patient's body necessary to prevent or combat the infection. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or theoretically, by calculating bioavailability. The amount of an active agent sufficient to inhibit viral infection in vitro may be determined with a conventional assay for viral infectivity such as a replicon based assay, which has been described in the literature.
Pharmaceutical compositions/combinations and methods of treatment in which a compound or salt of Formula I is provided together with one or more additional active agents are included herein. In preferred embodiments a compound of Formula I is provided together with an NS3 protease inhibitor, either in a single pharmaceutical composition or a in separate dosage forms with instructions to the patient to use the compound of Formula I and additional active agent together. In certain embodiments, the additional active agent (or agents) is an HCV protease inhibitor or HCV polymerase inhibitor.
According to the methods of the invention, the compound or pharmaceutically acceptable salt of Formula I and at least one additional active agent may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the compound or salt of Formula I and an additional active agent sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.
Methods of treatment and pharmaceutical combinations including compounds or pharmaceutically acceptable salts of Formula I described herein together with any one or combination of the following compounds and substances as an additional active agent are provided by the disclosure:
Caspase inhibitors: IDN 6556 (Idun Pharmaceuticals).
Cyclophilin Inhibitors: for example, NIM811 (Novartis), SCY-635 (Scynexis), and DEBIO-025 (Debiopharm).
Cytochrome P450 monooxygenase inhibitors: ritonavir (WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
Glucocorticoids: hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, paramethasone, betamethasone, and dexamethasone.
HCV Protease Inhibitors: for example ACH-1625 and ACH-2684, ABT-450 (Abbott), ACL-181 and AVL-192 (Avila), BI-335 (Boehringer Ingelheim), BMS-032 (Bristol Meyers Squibb), boceprevir (Merck), TMC-435, MK-7152 (Merck), GS-9256 (Gilead), GS-9451 (Gilead), R7227 (Roche), VX-950 (telaprevir, Vertex), VX-985 (Vertex), TMC-435 (Tibotec), GW-433908 (prodrug of Amprenavir, Glaxo/Vertex), indinavir (CRIXIVAN, Merck), and ITMN-191 (Intermune/Array Biopharma).
Immunomodulatory compounds: thalidomide, IL-2, hematopoietins, IMPDH inhibitors, for example Merimepodib (Vertex Pharmaceuticals Inc.), interferon, including natural interferon (such as OMNIFERON, Viragen and SUMIFERON, Sumitomo, a blend of natural interferons), natural interferon alpha (ALFERON, Hemispherx Biopharma, Inc.), interferon alpha nl from lymphblastoid cells (WELLFERON, Glaxo Wellcome), oral alpha interferon, Peg-interferon, Peg-interferon alfa 2a (PEGASYS, Roche), recombinant interferon alfa 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX, Aradigm), Peg-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis, PEGINTRON, Schering), recombinant interferon alfa 2b (INTRON A, Schering), pegylated interferon alfa 2b (PEGINTRON, Schering, VIRAFERONPEG, Schering), interferon beta-1a (REBIF, Serono, Inc. and Pfizer), consensus interferon alpha (INFERGEN, Valeant Pharmaceutical), interferon gamma-1b (ACTIMMUNE, Intermune, Inc.), un-pegylated interferon alpha, alpha interferon, and its analogs, and synthetic thymosin alpha 1 (ZADAXIN, SciClone Pharmaceuticals Inc.), and lamdba interferon (BMS)
Immunosupressants: sirolimus (RAPAMUNE, Wyeth).
Interleukins: (IL-1, IL-3, IL-4, IL-5, IL-6, IL-10, IL-11, IL-12), LIF, TGF-beta, TNF-alpha) and other low molecular weight factors (e.g. AcSDKP, pEEDCK, thymic hormones, and minicytokines)
Interferon Enhancers: EMZ702 (Transition Therapeutics)
IRES inhibitors: VGX-410C (VGX Pharma)
Monoclonal and Polyclonal antibodies: XTL-6865 (XTL), HuMax-HepC (Genmab), Hepatitis C Immune Globin (human) (CIVACIR, Nabi Biopharmaceuticals)
Nucleoside analogues: IDX-184 (Idenix), PSI-7977 and PSI-938 (Pharmasset), INX-189 (Inhibitex), R7128 (Roche), R7348 (Roche), GS-6620 (Gilead), TMC-649 (Tibotec), Lamivudine (EPIVIR, 3TC, GlaxoSmithKline), MK-0608 (Merck), zalcitabine (HIVID, Roche US Pharmaceuticals), ribavirin (including COPEGUS (Roche), REBETOL (Schering), VILONA (ICN Pharmaceuticals, and VIRAZOLE (ICN Pharmaceuticals), and viramidine (Valeant Pharmaceuticals), an amidine prodrug of ribavirin. Combinations of nucleoside analogues may also be employed.
Non-nucleoside inhibitors: PSI-6130 (Roche/Pharmasset), ABT-333 and ABT-072 (Abbott), delaviridine (RESCRIPTOR, Pfizer), PF-868554 (Pfizer), GSK-852 (GlaxoSmithKline), IDX-325 (Idenix), ANA-598 (Anadys), VX-222 and VX-759 (Vertex), MK-3281 (Merck), BI-127 (Boehringer Ingelheim), BMS-325 (Bristol Meyers), and HCV-796 (Viropharm)
NS4a inhibitors: for example ACH-1095. US patent application no. US2007/0004711 is hereby incorporated by reference in its entirety for its teachings regarding HCV inhibitors and U.S. patent application Ser. No. 12/125,554 at pages 45-90 is hereby incorporated by reference for its teachings regarding HCV inhibitors.
NS5a inhibitors: ACH-2928 (Achillion), AZD7295 (Arrow Therapeutics), BMS-790052 (Bristol-Myers Squibb), EDP-239 (Enanta), PPI-461 and PPI-1301 (Presidio).
NS5b inhibitors: INX-181, IDX-375, MK-3281, PSI-7977, PSI-7851, PSI-938, RG-9190, VX-222 (Vertex), and BMS-791325 (Bristol Myers Squibb).
P7 protein inhibitor: amantadine (SYMMETREL, Endo Pharmaceuticals, Inc.)
Polymerase inhibitors: NM283 (valopicitabine) (Idenix) and NM 107 (Idenix).
Protease inhibitors: BILN-2061 (Boehringer Ingelheim), GW-433908 (prodrug of Amprenavir, Glaxo/Vertex), indinavir (CRIXIVAN, Merck), ITMN-191 (Intermune/Array Biopharma), VX950 (Vertex) and combinations comprising one or more of the foregoing protease inhibitors.
RNA interference: SIRNA-034 RNAi (Sirna Therapeutics)
Therapeutic Vaccines: IC41 (Intercell), IMN-0101 (Imnogenetics), GI 5005 (Globeimmune), Chronvac-C (Tripep/Inovio), ED-002 (Imnogenetics), Hepavaxx C (ViRex Medical)
TNF agonists: adalimumab (HUMIRA, Abbott), entanercept (ENBREL, Amgen and Wyeth), infliximab (REMICADE, Centocor, Inc.)
Tubulin inhibitors: Colchicine
Sphingosine-1-phosphate receptor modulators: FTY720 (Novartis)
TLR agonists: ANA-975 (Anadys Pharmaceuticals), ANA-773 (Anadys Pharmaceuticals), TLR7 agonist (Anadys Pharmaceuticals), CPG10101 (Coley), and TLR9 agonists including CPG 7909 (Coley)
Cyclophilin Inhibitors: NIM811 (Novartis) and DEBIO-025 (Debiopharm)
Patients receiving hepatitis C medications are typically given interferon together with another active agent. Thus, methods of treatment and pharmaceutical combinations in which a compound of the invention is provided together with an interferon, such as pegylated interferon alfa 2a, as the additional active agents are included as embodiments. Similarly, methods and pharmaceutical combinations in which ribavirin is an additional active agent are provided herein.
Additionally, methods and pharmaceutical combinations in which an NS3 protease inhibitor is the additional active agent are provided herein. The NS3 protease inhibitor may be selected from the group ACH-1625, ACH-2684, ABT-450, ACL-181, AVL-192, BI-335, BMS-032, boceprevir, TMC-435, MK-7152, GS-9256, GS-9451, R7227, VX-950, VX-985, TMC-435, GW-433908, indinavir, and ITMN-191.
Methods of inhibiting HCV replication in vivo comprising providing a compound or pharmaceutically acceptable salt of Formula I to a patient infected with HCV, a concentration of the compound or salt of Formula I sufficient to inhibit HCV replicon replication in vitro are included herein. In this instance the concentration includes an in vivo concentration, such as a blood or plasma concentration. The concentration of compound sufficient to inhibit HCV replicon replication in vitro may be determined from an assay of replicon replication such as the assay provided in Example 2, herein.
Methods of treatment include providing certain dosage amounts of a compound or pharmaceutically acceptable salt of Formula I to a patient. Dosage levels of each active agent of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single unit dosage form will vary depending upon the patient treated and the particular mode of administration. In certain embodiments about 0.1 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 300 to about 600 mg of a compound of Formula I and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 300 to about 600 mg of a compound of an additional active agent, for example an NS3 protease inhibitor such as a compound of Formula II are provided daily to a patient. It is preferred that each unit dosage form contains less than 1200 mg of active agent in total. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most infectious disorders, a dosage regimen of 4 times daily or less is preferred and a dosage regimen of 1 or 2 times daily is particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy.
Packaged Formulations
Methods comprising providing a compound or salt of a Chk2 inhibitor, such as a compound of Formula I, in a container together with instructions for using the compound to treat a patient suffering from HCV infection are included herein.
Packaged pharmaceutical compositions/combinations are also included herein. Such packaged combinations include a Chk2 inhibitor, such as a compound of Formula I, in a container together with instructions for using the combination to treat or prevent a viral infection, such as a HCV infection, in a patient. Pharmaceutical combinations include at least one additional active agent. In certain embodiments, the additional active agent is an NS3 protease inhibitor.
The packaged pharmaceutical combination may include a Chk2 inhibitor, such as a compound of Formula I, and an additional active agent provided simultaneously in a single dosage form, concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the Chk2 inhibitor, such as a compound of Formula I, and the additional active agent are within the bloodstream of the patient.
EXAMPLES
General Methods
All chemicals used in synthetic examples 1-## were purchased from Sigma-Aldrich Chemicals, Co. or Fisher Scientific and directly used without further purification. 1H and 13C NMR spectra were acquired on Varian 300 spectrometer at 25° C., and chemical shifts (δ in ppm) are given relative to that of Me4Si (TMS, δ 0.00 ppm) or with the solvent reference relative to TMS employed as the internal standard (CDCl3δ 7.26; D6-DMSO δ 2.50 ppm). Data are reported as follow: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) broad (b)], coupling constants [Hz], integration. HPLC was performed on Rainin SD-300 or Varian ProStar equipped with a single wavelength UV detector at 214 nm and linear gradients. Analytical HPLC was performed on a Varian C18 column (Microsorb 60-8, 4.6×250 mm) at a flow rate of 1 mL/min. Semi-preparative HPLC was performed on a Varian C18 column (Microsorb 60-8, 10.0×250 mm) at a flow rate of 5 mL/min. Preparative HPLC was routinely performed on a Varian C18 column (Microsorb 60-8, 21.4×250 mm) at a flow rate of 20 mL/min. The solvent system used on linear gradients was water with 0.075% TFA (solvent A) vs. acetonitrile with 0.075% TFA (solvent B). Silica gel used in flash column chromatography was obtained from Sorbent Technologies (Atlanta, Ga.). Analytical thin-layer chromatography (TLC) was carried out using Silica Gel 60 F254 precoated plates G/UV254 plates (Merck, 0.25 mm thickness). TLC Rf values are reported. Visualization was accomplished by irradiation with a UV lamp and/or staining with ceric ammonium molybdate (CAM) solution. LC-MS spectra were taken on Thermo Finnigan Navigator LC/MS-ESI or APCI.




Example 1
Preparation of (E)-N-(4-(1-(2-carbamimidoylhydrazono)ethyl)phenyl)-5-methoxy-1H-indole-2-carboxamide




5-Methoxy-1H-indole-2-carboxylic acid and 4′-aminoacetophenone are combined according to general synthetic scheme 1 (steps (i) and (ii)), to obtain the product. tR 14.5 min (20-60%, CH3CN, 20 min); MS (m/z) 365 (MH+).
Example 2
Preparation of (E)-N-(4-(1-(2-carbamimidoylhydrazono)ethyl)phenyl)-7-nitro-1H-indole-2-carboxamide




5-Nitro-1H-indole-2-carboxylic acid and 4′-aminoacetophenone were combined according to synthetic scheme 1 (steps (i) and (ii)), to obtain the product. tR 18.8 min (20-70%, CH3CN, 25 min); MS (m/z) 397 (M+).
Example 3
Preparation of (E)-N-(4-(1-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)ethyl)phenyl)-7-nitro-1H-indole-2-carboxamide




7-nitro-1H-indole-2-carboxylic acid and 4′-aminoacetophenone were combined according to general procedure B (steps (i) and (ii)), to obtain the product, tR 16.0 min (20-80%, CH3CN, 20 min); MS (m/z) 405 (M+).
Example 4
Preparation of (E)-N-(4-(1-(2-carbamimidoylhydrazono)ethyl)phenyl)-5-methoxy-7-nitro-1H-indole-2-carboxamide




5-Acetyl-1H-indole-2-carboxylic acid and 4′-aminoacetophenone were combined according to synthetic scheme 1 B (steps (i) and (ii)), to obtain the product. tR 15.5 min (10-90% CH3CN in H2O, 20 min); MS (m/z) 410 (MH+).
Example 5
Preparation of (E)-5-acetyl-N-(4-(1-(2-carbamimidoylhydrazono)ethyl)phenyl)-1H-indole-2-carboxamide




5-(2-Methyl-[1,3]dithian-2-yl)-1H-indole-2-carboxylic acid prepared by the method described by Kumar and Dev (Tetrahedron Letters (1983) 24(12):1289-1292) and 4′-aminoacetophenone were combined according to synthetic scheme 1 B (steps (i) and (ii)). After 1,3-dithiane deprotection by the DMP oxidation procedure described by Langille et al. (J. S. Org. Lett. (2003) 5(4:575-578), the pure monohydrozone was obtained by HPLC purification. tR 22.03 min (15-45% CH3CN in H2O, 40 min, semiprep); MS (m/z) 377 (MH+).
Example 6
Preparation of (E)-N-(5-(2-carbamimidoylhydrazono)-5,6,7,8-tetrahydronaphthalen-2-yl)-7-nitro-1H-indole-2-carboxamide




7-Nitro-1H-indole-2-carboxylic acid and 6-Amino-3,4-dihydro-2H-naphthalen-1-one were combined according to synthetic scheme 1 (steps (i) and (ii)), to obtain the product after HPLC purification. tR 15.71 min (20-70% CH3CN in H2O, 20 min); MS (m/z) 406 (MH+).
Example 7
Preparation of (E)-5-(1-(2-carbamimidoylhydrazono)ethyl)-N-(quinolin-6-yl)-1H-indole-2-carboxamide




5-Acetyl-1H-indole-2-carboxylic acid and 6-amino-quinoline were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtain the pure product after HPLC purification. tR 13.77 min (10-50% CH3CN in H2O, 20 min); MS (m/z) 386 (MH+).
Example 8
Preparation of (E)-5-(1-(2-carbamimidoylhydrazono)ethyl)-N-(1H-indol-4-yl)-1H-indole-2-carboxamide




5-Acetyl-1H-indole-2-carboxylic acid and 4-amino-indole were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtain the pure product after HPLC purification. tR 15.57 min (10-60% CH3CN in H2O, 20 min); MS (m/z) 374 (MH+).
Example 9
(E)-5-(1-(2-carbamimidoylhydrazono)ethyl)-N-(2-methyl-1H-indol-5-yl)-1H-indole-2-carboxamide




5-Acetyl-1H-indole-2-carboxylic acid and 5-amino-2-methyl-1H-indole were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtained the pure product after HPLC purification. tR 15.57 min (10-60% CH3CN in H2O, 20 min); MS (m/z) 388 (MH+).
Example 10
Preparation of 5-(1-(2-carbamimidoylhydrazono)butyl)-N-(1H-indol-6-yl)-1H-indole-2-carboxamide




5-Butyryl-1H-indole-2-carboxylic acid and 6-amino-1H-indole were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtained two pure isomers after HPLC purification. PV1518: tR 14.40 min, MS (m/z) 406 (MH+) and PV1519: tR 16.73 min (30-50% CH3CN in H2O, 20 min); MS (m/z) 406 (MH+).
Example 11
Preparation of (E)-N-(4-(1-(2(N-hydroxycarbamimidoyl)hydrazono)ethylphenyl)-5-methoxy-1H-indole-2-carboxamide




5-Methoxy-1H-indole-2-carboxylic acid (4-acetyl-phenyl)-amide, made from 5-Methoxy-1H-indole-2-carboxylic acid and 4-acetyl phenylamine, and N-hydroxy-N′-aminoguanidine PTSA salt, prepared by following method discussed in Tai, et al. (J. Med. Chem. (1983) 26:1326-1329) were combined according to synthetic scheme, to obtain the pure product after purification by reverse phase HPLC: tR 20.5 min (20-60% CH3CN in H2O, 25 min); MS (m/z) 381 (MH+).
Example 12
(Z)—N-(1H-benzo[D]imidazol-6-yl)-5-(1-(2-carbamimidoylhydrazono)ethyl)-1H-indole-2-carboxamide




5-Acetyl-1H-indole-2-carboxylic acid and 5-amino-benzoimidazole were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtain the pure product after HPLC purification. tR 14.71 min (10-40% CH3CN in H2O, 20 min); MS (m/z) 375 (MH+).
Example 13
Preparation of (E)-5-(1-(2-carbamimidoylhydrazono)-3-methylbutyl)-N-(1H-indol-6-yl)-1H-indole-2-carboxamide




A. Synthesis of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (Froshauer, S. A. et al., U.S. Pat. No. 5,981,762 (1999)): 3-Bromo-1H-indole-2-carboxylic acid ethyl ester (536 mg, 2.0 mmol), is prepared by following the method given by Elliott, J. D. et al., (U.S. Pat. No. 5,684,032 (1997)) is dissolved in nitromethane (10 mL) and cooled to 0° C. AlCl3 is added to the flask. Then a solution of isovaleryl chloride (0.295 mL, 2.4 mmol) in nitromethane (2 mL) was added dropwise to the flask. The mixture is allowed to come to room temperature and stirred for 18 hours, and then cooled to 0° C. 20 mL ice-water is added and extracted with CH2Cl2 (4×20 mL). The combined organic phase is washed with saturated brine (20 mL), 1N NaHCO3 (20 mL) and saturated brine (2×20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give yellow solid. It is then purified by flash column chromatography eluted with hexane:ethyl acetate (6:1) to give 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (468 mg, 67%) as light yellow solid. 1H NMR (300 MHz, DMSO-d6) 612.60 (brs, 1H); 8.20 (d, J=1.2 Hz, 1H), 7.97 (dd, J=8.7, 1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 4.41 (q, J=6.9 Hz, 2H), 2.98 (d, J=6.9 Hz, 2H), 2.20 (m, 1H), 1.39 (t, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 6H). EIMS m/z 352.0 (M++H).
B. Synthesis of 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid. DMF (5 mL) and water (0.625 mL) are added to the mixture of 3-Bromo-5-(3-methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester (408 mg, 1.1 mmol), ammonium formate (110 mg, 1.7 mmol), and 10% Pd/C (200 mg). The mixture is slightly shaken at room temperature for 70 minutes and then filtered through celite. The solvent is evaporated under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid ethyl ester as light yellow liquid as crude product with the purity of 90%; EI-MS m/z 274.1 (M++H). The crude ethyl ester is dissolved in dioxane (10 mL), then a solution of LiOH.H2O (195 mg, 4.6 mmol) in water (5 mL) is added to the flask. The mixture is stirred at room temperature for 2 days. Dioxane is stripped under vacuum. 10 mL water is added and extracted with CH2Cl2. The aqueous phase is then acidified with 6N HCl and extracted with CH2Cl2. The CH2Cl2 phase is then washed with saturated brine and dried over anhydrous Na2SO4. Solvent is removed under vacuum to give 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid (250 mg, 88% for two steps) as white solid. EIMS m/z 246.1 (M++H).
C. 5-(3-Methyl-butyryl)-1H-indole-2-carboxylic acid and 6-amino-1H-indole were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtained two isomers after HPLC purification. (E)-5-(1-(2-carbamimidoylhydrazono)-3-methylbutyl)-N-(1H-indol-6-yl)-1H-indole-2-carboxamide: tR 14.85 min (20-80% CH3CN in H2O, 20 min); MS (m/z) 416 (MH+); (E)-5-(1-(2-carbamimidoylhydrazono)-3-methylbutyl)-N-(1H-indol-6-yl)-1H-indole-2-carboxamide Isomer: tR 16.23 min (20-80% CH3CN in H2O, 20 min); MS (m/z) 416 (MH+).
Example 14
Preparation of (E)-5-(1-(2-carbamimidoylhydrazono)ethyl)-N-(2-methylquinolin-7-yl)-1H-indole-2-carboxamide (PV-1549)




5-Acetyl-1H-indole-2-carboxylic acid and 6-amino-2-methyl-quinoline were combined according to synthetic scheme 1 (steps (i) and (ii)) to obtain the pure product after HPLC purification. tR 12.63 min (10-60% CH3CN in H2O, 20 min); MS (m/z) 400 (MH+).
Example 15
Additional Compounds
The following compounds have been prepared by the methods set forth in Examples 1-14 and Scheme 1.
Example 15a
N-(4-(2-amino-1H-imidazol-5-yl)phenyl)-5-methoxy-1H-indole-2-carboxamide (16)




Example 15b
(E)-5-(1-(2-carbamimidoylhydrazono)ethyl)-N-(4-(piperidin-1-yl)phenyl)-1H-indole-2-carboxamide (17)




Example 15c
5-((E)-1-(2-((Z)—N′-hydroxycarbamimidoyl)hydrazono)ethyl)-N-(4-(piperidin-1-yl)phenyl)-1H-indole-2-carboxamide (18)




Example 16
Assay for Identifying Compounds which Inhibit HCV Replication
Compounds claimed herein are tested for the ability to inhibit viral replication of the Hepatitis C replicon in cultured cells in which the HCV replicon construct has been incorporated. The HCV replicon system was described by Bartenschlager, et al (Science (1999) 285:110-113) and Krieger, N. V. et al., (J. Virol. (2001) 75:4614-4624). The replicon system is predictive of in vivo anti-HCV activity; compounds that are active in humans uniformly evidence activity in the replicon assay.
The methods used to identify compounds are described at: http://niaid-aacf.org/protocols/HCV.htm.
The assay used the cell line Huh7 ET (luc-ubi-neo/ET), which contains a HCV RNA replicon with a stable luciferase (LUC) reporter. This particular construct is similar to the cell line 5-2 described by Krieger, but contains additional modifications that make the cell line more robust and provide stable LUC expression for antiviral screening. This composition of the replicon is shown diagrammatically in FIG. 1.
Primary HCV RNA Replicon Assay
Drugs are added in triplicate at a single high-test concentration of 20 μM and the effect on HCV RNA-derived LUC activity and cytotoxicity is determined. Human interferon alpha-2b is included in each run as a positive control compound. Subconfluent cultures of the ET line are plated out into 96-well plates that are dedicated for the analysis of cell numbers (cytotoxicity) or antiviral activity and the next day drugs are added to the appropriate wells. Cells are processed 72 hr later when the cells are still subconfluent. Compounds that reduced the LUC signal by 50% or more relative to the untreated cell controls are considered active. Compound cytotoxicity is assessed as the percent viable cells relative to the untreated cell controls.
HCV RNA Replicon Confirmatory Assay
The HCV RNA replicon confirmatory assay is used to examine the effects of compounds at five half-log concentrations each. Human interferon alpha-2b is included in each run as a positive control compound. Subconfluent cultures of the ET line are plated out into 96-well plates that are dedicated for the analysis of cell numbers (cytotoxicity) or antiviral activity and the next day drugs are added to the appropriate wells. Cells are processed 72 hr later when the cells are still subconfluent. Compound EC50 and EC90 values (antiviral activity) are derived from HCV RNA levels assessed as either HCV RNA replicon-derived LUC activity or as HCV RNA using TaqMan RT-PCR. Compound IC50 values (cytotoxicity) are calculated using CytoTox-1 (Promega), a colorimetric assay used as an indicator of cell numbers and cytotoxicity when the LUC assay system is employed, while ribosomal (rRNA) levels determined via TaqMan RT-PCR are used as an indication of cell numbers in the RNA-based assay.
HCV Replicon Assay Results
The concentration-response curves are presented in FIGS. 2 and 3 for select compounds tested in the luciferase based HCV replicon assay described in the preceding paragraph. FIG. 2 shows the effect of increasing concentrations of Compound 14 on HCV replication and cell viability. FIG. 3 shows the effect of increasing concentrations of Compound 10 on HCV replication and cell viability. Compound 10 was dissolved in dH2O: DMSO. Compound 14 was dissolved in dH2O.
FIG. 4 shows a crystal structure of Compound 14 (PV-1549) in the catalytic domain of the CHK2 kinase. Crystallographic data processing, refinement statistics, and other details are givent in Table 1.







TABLE 1







REFINEMENT.








 PROGRAM:
REFMAC 5.5.0104


 AUTHORS:
MURSHUDOV, VAGIN, DODSON








  REFINEMENT TARGET:
MAXIMUM LIKELIHOOD







 DATA USED IN REFINEMENT.










 RESOLUTION RANGE HIGH
(ANGSTROMS):
2.55



 RESOLUTION RANGE LOW
(ANGSTROMS):
50.00



 DATA CUTOFF
(SIGMA(F)):
NONE



 COMPLETENESS FOR RANGE
(%):
99.86










 NUMBER OF REFLECTIONS:
13938








FIT TO DATA USED IN REFINEMENT.









 CROSS-VALIDATION METHOD:
THROUGHOUT



 FREE R VALUE TEST SET SELECTION:
RANDOM











 R VALUE
(WORKING + TEST SET):
0.22534



 R VALUE
(WORKING SET):
0.22281



 FREE R VALUE:

0.27320











 FREE R VALUE TEST SET SIZE
(%):
5.0



 FREE R VALUE TEST SET COUNT:

739








FIT IN THE HIGHEST RESOLUTION BIN.









 TOTAL NUMBER OF BINS USED:
20



 BIN RESOLUTION RANGE HIGH:
2.551



 BIN RESOLUTION RANGE LOW:
2.617











 REFLECTION IN BIN
(WORKING SET):
998



 BIN COMPLETENESS
(WORKING + TEST) (%):
98.79



 BIN R VALUE
(WORKING SET):
0.353










 BIN FREE R VALUE SET COUNT:
62



 BIN FREE R VALUE:
0.413








NUMBER OF NON-HYDROGEN


ATOMS USED IN REFINEMENT.









 ALL ATOMS:
2352



B VALUES.












 FROM WILSON PLOT
(A**2):
NULL



 MEAN B VALUE
(OVERALL, A**2):
52.093








 OVERALL ANISOTROPIC B VALUE.










 B11
(A**2):
−0.20



 B22
(A**2):
−0.20



 B33
(A**2):
0.30



 B12
(A**2):
−0.10



 B13
(A**2):
0.00



 B23
(A**2):
0.00








ESTIMATED OVERALL COORDINATE ERROR.










 ESU BASED ON R VALUE
(A):
0.417



 ESU BASED ON FREE R VALUE
(A):
0.291



 ESU BASED ON MAXIMUM LIKELIHOOD
(A):
0.223



 ESU FOR B VALUES BASED
(A**2):
10.209



 ON MAXIMUM LIKELIHOOD












CORRELATION COEFFICIENTS.




 CORRELATION COEFFICIENT FO-FC:
0.945



 CORRELATION COEFFICIENT FO-FC FREE:
0.927











RMS DEVIATIONS FROM IDEAL VALUES
COUNT
RMS
WEIGHT











 BOND LENGTHS REFINED ATOMS
(A):
2356;
0.014;
0.022


 BOND LENGTHS OTHERS
(A):
1623;
0.001;
0.020


 BOND ANGLES REFINED ATOMS
(DEGREES):
3182;
1.349;
1.998


 BOND ANGLES OTHERS
(DEGREES):
3980;
0.849;
3.005


 TORSION ANGLES, PERIOD 1
(DEGREES):
283;
5.657;
5.000


 TORSION ANGLES, PERIOD 2
(DEGREES):
99;
36.895;
24.848


 TORSION ANGLES, PERIOD 3
(DEGREES):
444;
17.076;
15.000


 TORSION ANGLES, PERIOD 4
(DEGREES):
10;
20.741;
15.000


 CHIRAL-CENTER RESTRAINTS
(A**3):
359;
0.073;
0.200











 GENERAL PLANES REFINED ATOMS
(A):
2541;
0.005;
0.021


 GENERAL PLANES OTHERS
(A):
454;
0.001;
0.020











ISOTROPIC THERMAL FACTOR RESTRAINTS.

COUNT
RMS
WEIGHT


 MAIN-CHAIN BOND REFINED ATOMS
(A**2):
1419;
0.743;
1.500


 MAIN-CHAIN BOND OTHER ATOMS
(A**2):
573;
0.094;
1.500


 MAIN-CHAIN ANGLE REFINED ATOMS
(A**2):
2301;
1.380;
2.000


 SIDE-CHAIN BOND REFINED ATOMS
(A**2):
937;
1.519;
3.000


 SIDE-CHAIN ANGLE REFINED ATOMS
(A**2):
881;
2.543;
4.500







NCS RESTRAINTS STATISTICS








 NUMBER OF NCS GROUPS:
NULL








TWIN DETAILS



 NUMBER OF TWIN DOMAINS:
NULL








TLS DETAILS



 NUMBER OF TLS GROUPS:
NULL







 BULK SOLVENT MODELLING.








  METHOD USED:
MASK







  PARAMETERS FOR MASK CALCULATION









  VDW PROBE RADIUS:
1.20



  ION PROBE RADIUS:
0.80



  SHRINKAGE RADIUS:
0.80








 OTHER REFINEMENT REMARKS:


 HYDROGENS HAVE BEEN ADDED


 IN THE RIDING POSITIONS








 U VALUES:
REFINED INDIVIDUALLY










LINKR
LYS A 253
ASN A 269
gap















CRYST1
90.322
90.322
92.977
90.00
90.00
120.00
P 32 2 1













SCALE1
0.011072
0.006392
0.000000
0.00000



SCALE2
0.000000
0.012784
0.000000
0.00000



SCALE3
0.000000
0.000000
0.010755
0.00000



























TABLE 2







ATOM
1
N
VAL
A
211
9.704
−66.509
−3.990
1.00
59.69
N


ATOM
2
CA
VAL
A
211
10.385
−66.598
−2.646
1.00
60.04
C


ATOM
4
CB
VAL
A
211
10.989
−68.012
−2.359
1.00
59.80
C


ATOM
6
CG1
VAL
A
211
9.891
−69.035
−2.116
1.00
59.27
C


ATOM
10
CG2
VAL
A
211
11.946
−68.457
−3.489
1.00
59.03
C


ATOM
14
C
VAL
A
211
11.532
−65.606
−2.518
1.00
60.02
C


ATOM
15
O
VAL
A
211
11.997
−65.062
−3.514
1.00
60.65
O


ATOM
19
N
TYR
A
212
11.998
−65.415
−1.286
1.00
59.74
N


ATOM
20
CA
TYR
A
212
13.157
−64.569
−1.003
1.00
59.52
C


ATOM
22
CB
TYR
A
212
13.311
−64.386
0.511
1.00
59.60
C


ATOM
25
CG
TYR
A
212
12.128
−63.707
1.174
1.00
59.77
C


ATOM
26
CD1
TYR
A
212
11.715
−62.434
0.778
1.00
60.12
C


ATOM
28
CE1
TYR
A
212
10.619
−61.802
1.404
1.00
60.51
C


ATOM
30
CZ
TYR
A
212
9.940
−62.452
2.434
1.00
60.56
C


ATOM
31
OH
TYR
A
212
8.878
−61.832
3.046
1.00
62.98
O


ATOM
33
CE2
TYR
A
212
10.326
−63.714
2.843
1.00
59.39
C


ATOM
35
CD2
TYR
A
212
11.421
−64.333
2.213
1.00
60.77
C


ATOM
37
C
TYR
A
212
14.441
−65.165
−1.574
1.00
59.11
C


ATOM
38
O
TYR
A
212
14.550
−66.377
−1.718
1.00
59.78
O


ATOM
40
N
PRO
A
213
15.415
−64.318
−1.937
1.00
58.48
N


ATOM
41
CA
PRO
A
213
16.614
−64.920
−2.509
1.00
57.79
C


ATOM
43
CB
PRO
A
213
17.364
−63.730
−3.147
1.00
57.55
C


ATOM
46
CG
PRO
A
213
16.723
−62.527
−2.656
1.00
58.12
C


ATOM
49
CD
PRO
A
213
15.336
−62.876
−2.211
1.00
58.50
C


ATOM
52
C
PRO
A
213
17.461
−65.610
−1.464
1.00
57.37
C


ATOM
53
O
PRO
A
213
17.402
−65.272
−0.276
1.00
57.60
O


ATOM
54
N
LYS
A
214
18.261
−66.556
−1.927
1.00
56.63
N


ATOM
55
CA
LYS
A
214
19.101
−67.370
−1.056
1.00
56.21
C


ATOM
57
CB
LYS
A
214
19.924
−68.363
−1.892
1.00
56.25
C


ATOM
60
CG
LYS
A
214
20.776
−69.324
−1.085
1.00
55.36
C


ATOM
63
CD
LYS
A
214
21.099
−70.544
−1.909
1.00
55.57
C


ATOM
66
CE
LYS
A
214
21.812
−71.608
−1.117
1.00
55.87
C


ATOM
69
NZ
LYS
A
214
22.203
−72.753
−1.990
1.00
56.18
N


ATOM
73
C
LYS
A
214
20.042
−66.551
−0.189
1.00
55.96
C


ATOM
74
O
LYS
A
214
20.142
−66.805
1.037
1.00
56.20
O


ATOM
76
N
ALA
A
215
20.744
−65.593
−0.809
1.00
54.77
N


ATOM
77
CA
ALA
A
215
21.747
−64.802
−0.079
1.00
53.99
C


ATOM
79
CB
ALA
A
215
22.507
−63.912
−1.011
1.00
53.78
C


ATOM
83
C
ALA
A
215
21.114
−63.991
1.037
1.00
53.43
C


ATOM
84
O
ALA
A
215
21.740
−63.742
2.042
1.00
54.14
O


ATOM
86
N
LEU
A
216
19.861
−63.606
0.870
1.00
53.32
N


ATOM
87
CA
LEU
A
216
19.115
−62.898
1.912
1.00
53.40
C


ATOM
89
CB
LEU
A
216
17.831
−62.314
1.316
1.00
53.41
C


ATOM
92
CG
LEU
A
216
16.896
−61.573
2.265
1.00
54.08
C


ATOM
94
CD1
LEU
A
216
17.552
−60.308
2.744
1.00
54.78
C


ATOM
98
CD2
LEU
A
216
15.578
−61.251
1.586
1.00
55.48
C


ATOM
102
C
LEU
A
216
18.750
−63.845
3.062
1.00
53.13
C


ATOM
103
O
LEU
A
216
19.023
−63.570
4.227
1.00
52.31
O


ATOM
105
N
ARG
A
217
18.112
−64.959
2.715
1.00
52.97
N


ATOM
106
CA
ARG
A
217
17.702
−65.955
3.712
1.00
52.47
C


ATOM
108
CB
ARG
A
217
16.960
−67.106
3.051
1.00
51.91
C


ATOM
111
CG
ARG
A
217
15.582
−66.743
2.529
1.00
50.50
C


ATOM
114
CD
ARG
A
217
15.006
−67.879
1.647
1.00
49.87
C


ATOM
117
NE
ARG
A
217
15.044
−69.171
2.358
1.00
46.94
N


ATOM
119
CZ
ARG
A
217
15.584
−70.296
1.905
1.00
44.78
C


ATOM
120
NH1
ARG
A
217
16.108
−70.383
0.688
1.00
45.58
N


ATOM
123
NH2
ARG
A
217
15.562
−71.374
2.673
1.00
46.22
N


ATOM
126
C
ARG
A
217
18.903
−66.489
4.505
1.00
52.60
C


ATOM
127
O
ARG
A
217
18.784
−66.780
5.703
1.00
52.26
O


ATOM
129
N
ASP
A
218
20.049
−66.594
3.843
1.00
52.51
N


ATOM
130
CA
ASP
A
218
21.301
−66.974
4.510
1.00
53.21
C


ATOM
132
CB
ASP
A
218
22.477
−66.844
3.538
1.00
53.69
C


ATOM
135
CG
ASP
A
218
23.762
−67.419
4.096
1.00
54.40
C


ATOM
136
OD1
ASP
A
218
23.982
−68.621
3.875
1.00
55.35
O


ATOM
137
OD2
ASP
A
218
24.564
−66.674
4.727
1.00
58.00
O


ATOM
138
C
ASP
A
218
21.643
−66.146
5.752
1.00
53.04
C


ATOM
139
O
ASP
A
218
22.199
−66.680
6.718
1.00
52.74
O


ATOM
141
N
GLU
A
219
21.361
−64.844
5.694
1.00
53.15
N


ATOM
142
CA
GLU
A
219
21.721
−63.902
6.767
1.00
53.21
C


ATOM
144
CB
GLU
A
219
22.298
−62.611
6.186
1.00
53.06
C


ATOM
147
CG
GLU
A
219
23.735
−62.684
5.815
1.00
53.19
C


ATOM
150
CD
GLU
A
219
24.314
−61.301
5.633
1.00
53.30
C


ATOM
151
OE1
GLU
A
219
24.683
−60.673
6.647
1.00
52.87
O


ATOM
152
OE2
GLU
A
219
24.402
−60.851
4.481
1.00
52.75
O


ATOM
153
C
GLU
A
219
20.559
−63.491
7.627
1.00
53.33
C


ATOM
154
O
GLU
A
219
20.779
−63.008
8.740
1.00
53.79
O


ATOM
156
N
TYR
A
220
19.343
−63.639
7.107
1.00
53.55
N


ATOM
157
CA
TYR
A
220
18.156
−63.122
7.754
1.00
54.35
C


ATOM
159
CB
TYR
A
220
17.707
−61.830
7.056
1.00
54.15
C


ATOM
162
CG
TYR
A
220
18.751
−60.715
7.062
1.00
53.15
C


ATOM
163
CD1
TYR
A
220
18.892
−59.862
8.159
1.00
53.30
C


ATOM
165
CE1
TYR
A
220
19.838
−58.833
8.172
1.00
51.77
C


ATOM
167
CZ
TYR
A
220
20.653
−58.645
7.074
1.00
51.76
C


ATOM
168
OH
TYR
A
220
21.601
−57.641
7.081
1.00
52.77
O


ATOM
170
CE2
TYR
A
220
20.529
−59.470
5.972
1.00
51.93
C


ATOM
172
CD2
TYR
A
220
19.585
−60.500
5.969
1.00
52.20
C


ATOM
174
C
TYR
A
220
17.002
−64.125
7.758
1.00
55.63
C


ATOM
175
O
TYR
A
220
16.797
−64.873
6.795
1.00
55.50
O


ATOM
177
N
ILE
A
221
16.269
−64.137
8.867
1.00
57.44
N


ATOM
178
CA
ILE
A
221
14.982
−64.809
8.973
1.00
59.07
C


ATOM
180
CB
ILE
A
221
14.742
−65.392
10.359
1.00
59.12
C


ATOM
182
CG1
ILE
A
221
15.752
−66.486
10.679
1.00
57.77
C


ATOM
185
CD1
ILE
A
221
15.931
−66.670
12.175
1.00
57.33
C


ATOM
189
CG2
ILE
A
221
13.304
−65.891
10.472
1.00
58.21
C


ATOM
193
C
ILE
A
221
13.912
−63.754
8.798
1.00
61.48
C


ATOM
194
O
ILE
A
221
13.863
−62.773
9.550
1.00
60.93
O


ATOM
196
N
MET
A
222
13.039
−63.972
7.822
1.00
64.73
N


ATOM
197
CA
MET
A
222
12.003
−63.000
7.478
1.00
67.28
C


ATOM
199
CB
MET
A
222
11.690
−63.050
5.981
1.00
67.73
C


ATOM
202
CG
MET
A
222
12.939
−62.977
5.081
1.00
70.06
C


ATOM
205
SD
MET
A
222
13.810
−61.407
5.173
1.00
75.87
S


ATOM
206
CE
MET
A
222
12.482
−60.248
4.721
1.00
72.41
C


ATOM
210
C
MET
A
222
10.730
−63.221
8.293
1.00
68.93
C


ATOM
211
O
MET
A
222
10.375
−64.355
8.634
1.00
69.11
O


ATOM
213
N
SER
A
223
10.053
−62.115
8.593
1.00
71.16
N


ATOM
214
CA
SER
A
223
8.869
−62.123
9.436
1.00
72.72
C


ATOM
216
CB
SER
A
223
9.251
−61.675
10.852
1.00
72.76
C


ATOM
219
OG
SER
A
223
8.222
−61.947
11.784
1.00
72.89
O


ATOM
221
C
SER
A
223
7.774
−61.233
8.831
1.00
74.35
C


ATOM
222
O
SER
A
223
7.682
−61.103
7.605
1.00
74.25
O


ATOM
224
N
LYS
A
224
6.968
−60.617
9.701
1.00
76.37
N


ATOM
225
CA
LYS
A
224
5.709
−59.976
9.311
1.00
77.89
C


ATOM
227
CB
LYS
A
224
4.846
−59.700
10.557
1.00
78.21
C


ATOM
230
CG
LYS
A
224
5.287
−58.499
11.409
1.00
79.48
C


ATOM
233
CD
LYS
A
224
4.624
−58.499
12.791
1.00
80.57
C


ATOM
236
CE
LYS
A
224
5.099
−57.331
13.650
1.00
80.78
C


ATOM
239
NZ
LYS
A
224
4.758
−56.019
13.022
1.00
81.60
N


ATOM
243
C
LYS
A
224
5.888
−58.683
8.534
1.00
78.85
C


ATOM
244
O
LYS
A
224
6.977
−58.108
8.493
1.00
79.38
O


ATOM
246
N
THR
A
225
4.792
−58.237
7.926
1.00
79.95
N


ATOM
247
CA
THR
A
225
4.736
−56.962
7.224
1.00
80.64
C


ATOM
249
CB
THR
A
225
3.646
−56.979
6.140
1.00
80.64
C


ATOM
251
OG1
THR
A
225
3.884
−58.080
5.256
1.00
80.64
O


ATOM
253
CG2
THR
A
225
3.639
−55.661
5.338
1.00
80.64
C


ATOM
257
C
THR
A
225
4.454
−55.832
8.209
1.00
81.30
C


ATOM
258
O
THR
A
225
3.713
−56.011
9.173
1.00
81.52
O


ATOM
260
N
LEU
A
226
5.066
−54.677
7.964
1.00
82.26
N


ATOM
261
CA
LEU
A
226
4.903
−53.492
8.812
1.00
82.89
C


ATOM
263
CB
LEU
A
226
6.276
−53.001
9.283
1.00
82.80
C


ATOM
266
CG
LEU
A
226
7.013
−53.974
10.215
1.00
82.80
C


ATOM
268
CD1
LEU
A
226
8.507
−53.651
10.329
1.00
82.21
C


ATOM
272
CD2
LEU
A
226
6.353
−53.991
11.587
1.00
82.54
C


ATOM
276
C
LEU
A
226
4.135
−52.381
8.076
1.00
83.57
C


ATOM
277
O
LEU
A
226
3.347
−51.664
8.689
1.00
83.23
O


ATOM
279
N
GLY
A
227
4.373
−52.250
6.769
1.00
84.56
N


ATOM
280
CA
GLY
A
227
3.577
−51.375
5.903
1.00
85.41
C


ATOM
283
C
GLY
A
227
3.666
−51.734
4.421
1.00
86.33
C


ATOM
284
O
GLY
A
227
4.271
−52.751
4.042
1.00
86.12
O


ATOM
286
N
SER
A
228
3.047
−50.896
3.585
1.00
87.47
N


ATOM
287
CA
SER
A
228
3.185
−50.990
2.114
1.00
88.36
C


ATOM
289
CB
SER
A
228
2.328
−52.135
1.546
1.00
88.37
C


ATOM
292
OG
SER
A
228
0.957
−51.935
1.829
1.00
88.44
O


ATOM
294
C
SER
A
228
2.833
−49.663
1.426
1.00
88.90
C


ATOM
295
O
SER
A
228
2.424
−48.699
2.088
1.00
89.00
O


ATOM
297
N
GLY
A
229
3.015
−49.616
0.103
1.00
89.40
N


ATOM
298
CA
GLY
A
229
2.649
−48.440
−0.696
1.00
89.53
C


ATOM
301
C
GLY
A
229
2.643
−48.742
−2.184
1.00
89.79
C


ATOM
302
O
GLY
A
229
2.528
−49.909
−2.590
1.00
90.11
O


ATOM
304
N
ALA
A
230
2.751
−47.696
−3.003
1.00
89.68
N


ATOM
305
CA
ALA
A
230
2.987
−47.884
−4.430
1.00
89.48
C


ATOM
307
CB
ALA
A
230
2.856
−46.554
−5.190
1.00
89.35
C


ATOM
311
C
ALA
A
230
4.395
−48.494
−4.596
1.00
89.31
C


ATOM
312
O
ALA
A
230
5.358
−48.028
−3.965
1.00
89.33
O


ATOM
314
N
CYS
A
231
4.483
−49.570
−5.389
1.00
88.81
N


ATOM
315
CA
CYS
A
231
5.751
−50.258
−5.763
1.00
88.31
C


ATOM
317
CB
CYS
A
231
6.805
−49.265
−6.328
1.00
88.65
C


ATOM
320
SG
CYS
A
231
6.395
−48.463
−7.955
1.00
90.98
S


ATOM
322
C
CYS
A
231
6.410
−51.187
−4.695
1.00
86.89
C


ATOM
323
O
CYS
A
231
7.030
−52.188
−5.067
1.00
86.84
O


ATOM
325
N
GLY
A
232
6.286
−50.880
−3.400
1.00
85.15
N


ATOM
326
CA
GLY
A
232
7.008
−51.644
−2.369
1.00
83.63
C


ATOM
329
C
GLY
A
232
6.314
−51.919
−1.043
1.00
82.13
C


ATOM
330
O
GLY
A
232
5.110
−51.689
−0.883
1.00
81.95
O


ATOM
332
N
GLU
A
233
7.114
−52.406
−0.090
1.00
80.29
N


ATOM
333
CA
GLU
A
233
6.632
−52.963
1.180
1.00
78.67
C


ATOM
335
CB
GLU
A
233
6.101
−54.372
0.930
1.00
78.75
C


ATOM
338
CG
GLU
A
233
5.300
−54.984
2.066
1.00
80.04
C


ATOM
341
CD
GLU
A
233
5.094
−56.498
1.893
1.00
81.89
C


ATOM
342
OE1
GLU
A
233
5.456
−57.033
0.817
1.00
82.69
O


ATOM
343
OE2
GLU
A
233
4.576
−57.156
2.835
1.00
82.47
O


ATOM
344
C
GLU
A
233
7.766
−53.014
2.224
1.00
76.64
C


ATOM
345
O
GLU
A
233
8.942
−53.141
1.871
1.00
76.15
O


ATOM
347
N
VAL
A
234
7.405
−52.916
3.503
1.00
74.24
N


ATOM
348
CA
VAL
A
234
8.372
−53.026
4.585
1.00
72.31
C


ATOM
350
CB
VAL
A
234
8.365
−51.774
5.468
1.00
72.25
C


ATOM
352
CG1
VAL
A
234
9.567
−51.781
6.383
1.00
71.92
C


ATOM
356
CG2
VAL
A
234
8.370
−50.540
4.623
1.00
72.34
C


ATOM
360
C
VAL
A
234
8.086
−54.253
5.457
1.00
70.71
C


ATOM
361
O
VAL
A
234
6.998
−54.369
6.028
1.00
69.97
O


ATOM
363
N
LYS
A
235
9.077
−55.151
5.547
1.00
68.82
N


ATOM
364
CA
LYS
A
235
9.000
−56.382
6.356
1.00
67.28
C


ATOM
366
CB
LYS
A
235
9.474
−57.589
5.540
1.00
67.57
C


ATOM
369
CG
LYS
A
235
8.467
−58.117
4.518
1.00
69.04
C


ATOM
372
CD
LYS
A
235
7.541
−59.179
5.125
1.00
71.23
C


ATOM
375
CE
LYS
A
235
6.432
−59.613
4.152
1.00
72.35
C


ATOM
378
NZ
LYS
A
235
6.939
−59.790
2.739
1.00
72.71
N


ATOM
382
C
LYS
A
235
9.838
−56.304
7.627
1.00
65.41
C


ATOM
383
O
LYS
A
235
10.804
−55.561
7.721
1.00
64.96
O


ATOM
385
N
LEU
A
236
9.455
−57.093
8.615
1.00
63.85
N


ATOM
386
CA
LEU
A
236
10.290
−57.304
9.794
1.00
62.20
C


ATOM
388
CB
LEU
A
236
9.436
−57.581
11.034
1.00
62.14
C


ATOM
391
CG
LEU
A
236
10.199
−57.880
12.335
1.00
62.51
C


ATOM
393
CD1
LEU
A
236
10.922
−56.627
12.868
1.00
60.92
C


ATOM
397
CD2
LEU
A
236
9.288
−58.481
13.411
1.00
60.30
C


ATOM
401
C
LEU
A
236
11.184
−58.498
9.498
1.00
60.71
C


ATOM
402
O
LEU
A
236
10.742
−59.479
8.875
1.00
60.24
O


ATOM
404
N
ALA
A
237
12.445
−58.398
9.918
1.00
58.82
N


ATOM
405
CA
ALA
A
237
13.373
−59.513
9.825
1.00
57.67
C


ATOM
407
CB
ALA
A
237
14.110
−59.456
8.513
1.00
57.41
C


ATOM
411
C
ALA
A
237
14.345
−59.525
11.012
1.00
56.66
C


ATOM
412
O
ALA
A
237
14.464
−58.536
11.752
1.00
56.37
O


ATOM
414
N
PHE
A
238
15.017
−60.653
11.210
1.00
55.52
N


ATOM
415
CA
PHE
A
238
16.030
−60.771
12.261
1.00
55.20
C


ATOM
417
CB
PHE
A
238
15.675
−61.873
13.253
1.00
55.71
C


ATOM
420
CG
PHE
A
238
14.365
−61.682
13.903
1.00
56.62
C


ATOM
421
CD1
PHE
A
238
14.281
−61.076
15.141
1.00
59.36
C


ATOM
423
CE1
PHE
A
238
13.047
−60.889
15.756
1.00
60.39
C


ATOM
425
CZ
PHE
A
238
11.894
−61.316
15.116
1.00
59.69
C


ATOM
427
CE2
PHE
A
238
11.983
−61.931
13.874
1.00
59.53
C


ATOM
429
CD2
PHE
A
238
13.209
−62.104
13.277
1.00
57.92
C


ATOM
431
C
PHE
A
238
17.348
−61.125
11.651
1.00
53.79
C


ATOM
432
O
PHE
A
238
17.422
−62.050
10.873
1.00
53.07
O


ATOM
434
N
GLU
A
239
18.392
−60.416
12.026
1.00
53.11
N


ATOM
435
CA
GLU
A
239
19.720
−60.772
11.562
1.00
53.36
C


ATOM
437
CB
GLU
A
239
20.670
−59.607
11.780
1.00
53.56
C


ATOM
440
CG
GLU
A
239
22.005
−59.711
11.059
1.00
55.35
C


ATOM
443
CD
GLU
A
239
22.933
−58.571
11.472
1.00
58.46
C


ATOM
444
OE1
GLU
A
239
22.382
−57.510
11.879
1.00
59.16
O


ATOM
445
OE2
GLU
A
239
24.185
−58.742
11.398
1.00
58.56
O


ATOM
446
C
GLU
A
239
20.198
−62.026
12.302
1.00
52.68
C


ATOM
447
O
GLU
A
239
20.225
−62.074
13.521
1.00
51.90
O


ATOM
449
N
ARG
A
240
20.543
−63.056
11.553
1.00
52.84
N


ATOM
450
CA
ARG
A
240
20.932
−64.326
12.158
1.00
53.23
C


ATOM
452
CB
ARG
A
240
21.216
−65.368
11.081
1.00
52.90
C


ATOM
455
CG
ARG
A
240
19.955
−65.799
10.334
1.00
51.69
C


ATOM
458
CD
ARG
A
240
20.286
−66.765
9.232
1.00
50.76
C


ATOM
461
NE
ARG
A
240
19.139
−66.983
8.349
1.00
50.02
N


ATOM
463
CZ
ARG
A
240
18.214
−67.934
8.501
1.00
49.70
C


ATOM
464
NH1
ARG
A
240
18.262
−68.790
9.509
1.00
49.42
N


ATOM
467
NH2
ARG
A
240
17.221
−68.022
7.633
1.00
49.65
N


ATOM
470
C
ARG
A
240
22.134
−64.159
13.077
1.00
54.12
C


ATOM
471
O
ARG
A
240
22.142
−64.686
14.185
1.00
54.74
O


ATOM
473
N
LYS
A
241
23.125
−63.388
12.648
1.00
54.86
N


ATOM
474
CA
LYS
A
241
24.331
−63.200
13.448
1.00
55.86
C


ATOM
476
CB
LYS
A
241
25.360
−62.335
12.688
1.00
56.93
C


ATOM
479
CG
LYS
A
241
26.798
−62.455
13.231
1.00
59.58
C


ATOM
482
CD
LYS
A
241
27.842
−61.801
12.312
1.00
63.23
C


ATOM
485
CE
LYS
A
241
27.811
−60.265
12.381
1.00
65.01
C


ATOM
488
NZ
LYS
A
241
28.757
−59.656
11.383
1.00
66.35
N


ATOM
492
C
LYS
A
241
24.109
−62.596
14.825
1.00
55.46
C


ATOM
493
O
LYS
A
241
24.903
−62.851
15.704
1.00
55.12
O


ATOM
495
N
THR
A
242
23.068
−61.774
15.007
1.00
55.69
N


ATOM
496
CA
THR
A
242
22.864
−61.053
16.277
1.00
55.89
C


ATOM
498
CB
THR
A
242
22.957
−59.514
16.064
1.00
56.33
C


ATOM
500
OG1
THR
A
242
21.863
−59.071
15.232
1.00
56.30
O


ATOM
502
CG2
THR
A
242
24.339
−59.101
15.471
1.00
53.37
C


ATOM
506
C
THR
A
242
21.521
−61.268
16.948
1.00
56.68
C


ATOM
507
O
THR
A
242
21.327
−60.868
18.088
1.00
56.11
O


ATOM
509
N
CYS
A
243
20.573
−61.849
16.229
1.00
57.80
N


ATOM
510
CA
CYS
A
243
19.209
−61.948
16.710
1.00
58.80
C


ATOM
512
CB
CYS
A
243
19.141
−62.852
17.935
1.00
58.56
C


ATOM
515
SG
CYS
A
243
19.704
−64.479
17.564
1.00
59.76
S


ATOM
517
C
CYS
A
243
18.598
−60.591
17.023
1.00
59.69
C


ATOM
518
O
CYS
A
243
17.820
−60.461
17.972
1.00
60.65
O


ATOM
520
N
LYS
A
244
18.941
−59.587
16.228
1.00
60.16
N


ATOM
521
CA
LYS
A
244
18.373
−58.273
16.413
1.00
60.73
C


ATOM
523
CB
LYS
A
244
19.461
−57.192
16.469
1.00
61.42
C


ATOM
526
CG
LYS
A
244
20.251
−57.118
17.809
1.00
63.19
C


ATOM
529
CD
LYS
A
244
19.399
−56.559
18.978
1.00
65.45
C


ATOM
532
CE
LYS
A
244
20.243
−55.851
20.072
1.00
66.52
C


ATOM
535
NZ
LYS
A
244
20.891
−56.802
21.036
1.00
66.32
N


ATOM
539
C
LYS
A
244
17.413
−58.007
15.266
1.00
60.83
C


ATOM
540
O
LYS
A
244
17.661
−58.381
14.104
1.00
60.86
O


ATOM
542
N
LYS
A
245
16.307
−57.364
15.612
1.00
60.45
N


ATOM
543
CA
LYS
A
245
15.317
−56.962
14.650
1.00
60.56
C


ATOM
545
CB
LYS
A
245
14.152
−56.295
15.374
1.00
61.00
C


ATOM
548
CG
LYS
A
245
13.379
−57.218
16.349
1.00
62.98
C


ATOM
551
CD
LYS
A
245
12.198
−56.453
16.990
1.00
65.29
C


ATOM
554
CE
LYS
A
245
11.545
−57.219
18.134
1.00
66.40
C


ATOM
557
NZ
LYS
A
245
10.325
−56.509
18.634
1.00
66.86
N


ATOM
561
C
LYS
A
245
15.935
−55.999
13.629
1.00
59.94
C


ATOM
562
O
LYS
A
245
16.765
−55.165
13.982
1.00
59.48
O


ATOM
564
N
VAL
A
246
15.570
−56.170
12.363
1.00
59.25
N


ATOM
565
CA
VAL
A
246
15.942
−55.239
11.305
1.00
58.95
C


ATOM
567
CB
VAL
A
246
17.127
−55.744
10.432
1.00
58.86
C


ATOM
569
CG1
VAL
A
246
18.401
−55.977
11.255
1.00
56.91
C


ATOM
573
CG2
VAL
A
246
16.723
−56.982
9.657
1.00
56.99
C


ATOM
577
C
VAL
A
246
14.716
−55.052
10.399
1.00
59.82
C


ATOM
578
O
VAL
A
246
13.777
−55.843
10.421
1.00
59.34
O


ATOM
580
N
ALA
A
247
14.716
−53.994
9.608
1.00
60.50
N


ATOM
581
CA
ALA
A
247
13.620
−53.765
8.696
1.00
61.12
C


ATOM
583
CB
ALA
A
247
13.103
−52.343
8.852
1.00
61.11
C


ATOM
587
C
ALA
A
247
14.156
−54.002
7.304
1.00
61.70
C


ATOM
588
O
ALA
A
247
15.312
−53.709
7.030
1.00
61.34
O


ATOM
590
N
ILE
A
248
13.325
−54.548
6.431
1.00
62.75
N


ATOM
591
CA
ILE
A
248
13.746
−54.823
5.059
1.00
63.81
C


ATOM
593
CB
ILE
A
248
13.925
−56.332
4.821
1.00
63.85
C


ATOM
595
CG1
ILE
A
248
15.112
−56.847
5.634
1.00
63.43
C


ATOM
598
CD1
ILE
A
248
15.448
−58.304
5.363
1.00
61.87
C


ATOM
602
CG2
ILE
A
248
14.150
−56.616
3.339
1.00
63.80
C


ATOM
606
C
ILE
A
248
12.760
−54.263
4.035
1.00
64.51
C


ATOM
607
O
ILE
A
248
11.656
−54.785
3.892
1.00
64.61
O


ATOM
609
N
LYS
A
249
13.178
−53.209
3.326
1.00
65.57
N


ATOM
610
CA
LYS
A
249
12.359
−52.575
2.286
1.00
66.27
C


ATOM
612
CB
LYS
A
249
12.725
−51.091
2.106
1.00
66.49
C


ATOM
615
CG
LYS
A
249
11.936
−50.335
1.022
1.00
66.47
C


ATOM
618
CD
LYS
A
249
10.677
−49.669
1.578
1.00
68.07
C


ATOM
621
CE
LYS
A
249
9.875
−48.937
0.481
1.00
69.24
C


ATOM
624
NZ
LYS
A
249
8.454
−48.611
0.890
1.00
71.19
N


ATOM
628
C
LYS
A
249
12.555
−53.312
0.975
1.00
66.70
C


ATOM
629
O
LYS
A
249
13.679
−53.481
0.507
1.00
66.44
O


ATOM
631
N
ILE
A
250
11.438
−53.738
0.399
1.00
67.51
N


ATOM
632
CA
ILE
A
250
11.424
−54.430
−0.865
1.00
68.46
C


ATOM
634
CB
ILE
A
250
10.501
−55.687
−0.809
1.00
68.77
C


ATOM
636
CG1
ILE
A
250
10.708
−56.445
0.513
1.00
69.23
C


ATOM
639
CD1
ILE
A
250
9.952
−57.745
0.610
1.00
70.43
C


ATOM
643
CG2
ILE
A
250
10.751
−56.593
−2.019
1.00
67.98
C


ATOM
647
C
ILE
A
250
10.896
−53.455
−1.906
1.00
69.21
C


ATOM
648
O
ILE
A
250
9.810
−52.898
−1.744
1.00
68.88
O


ATOM
650
N
ILE
A
251
11.681
−53.214
−2.947
1.00
70.25
N


ATOM
651
CA
ILE
A
251
11.218
−52.426
−4.072
1.00
71.13
C


ATOM
653
CB
ILE
A
251
12.084
−51.173
−4.347
1.00
71.33
C


ATOM
655
CG1
ILE
A
251
12.475
−50.463
−3.053
1.00
71.35
C


ATOM
658
CD1
ILE
A
251
13.696
−49.546
−3.238
1.00
71.11
C


ATOM
662
CG2
ILE
A
251
11.336
−50.210
−5.274
1.00
70.48
C


ATOM
666
C
ILE
A
251
11.267
−53.317
−5.296
1.00
72.00
C


ATOM
667
O
ILE
A
251
12.349
−53.771
−5.714
1.00
71.58
O


ATOM
669
N
SER
A
252
10.087
−53.553
−5.866
1.00
73.24
N


ATOM
670
CA
SER
A
252
9.941
−54.391
−7.059
1.00
74.18
C


ATOM
672
CB
SER
A
252
8.481
−54.813
−7.242
1.00
74.34
C


ATOM
675
OG
SER
A
252
7.701
−53.747
−7.750
1.00
74.43
O


ATOM
677
C
SER
A
252
10.403
−53.648
−8.303
1.00
74.62
C


ATOM
678
O
SER
A
252
10.321
−52.421
−8.361
1.00
74.70
O


ATOM
680
N
LYS
A
253
10.856
−54.405
−9.297
1.00
75.20
N


ATOM
681
CA
LYS
A
253
11.352
−53.837
−10.548
1.00
75.62
C


ATOM
683
CB
LYS
A
253
12.426
−54.745
−11.131
1.00
75.58
C


ATOM
686
CG
LYS
A
253
13.458
−55.164
−10.116
1.00
75.54
C


ATOM
689
CD
LYS
A
253
14.715
−55.637
−10.792
1.00
75.90
C


ATOM
692
CE
LYS
A
253
15.825
−55.808
−9.783
1.00
76.35
C


ATOM
695
NZ
LYS
A
253
17.142
−55.981
−10.443
1.00
75.89
N


ATOM
699
C
LYS
A
253
10.212
−53.648
−11.559
1.00
75.89
C


ATOM
700
O
LYS
A
253
10.443
−53.285
−12.717
1.00
76.23
O


ATOM
702
N
ASN
A
269
17.249
−44.062
−9.764
1.00
75.30
N


ATOM
703
CA
ASN
A
269
17.488
−45.492
−9.610
1.00
75.65
C


ATOM
705
CB
ASN
A
269
18.483
−46.009
−10.665
1.00
75.83
C


ATOM
708
CG
ASN
A
269
18.131
−47.422
−11.170
1.00
76.90
C


ATOM
709
OD1
ASN
A
269
17.815
−48.330
−10.388
1.00
77.75
O


ATOM
710
ND2
ASN
A
269
18.189
−47.603
−12.478
1.00
77.63
N


ATOM
713
C
ASN
A
269
17.966
−45.889
−8.204
1.00
75.30
C


ATOM
714
O
ASN
A
269
18.396
−45.064
−7.387
1.00
75.29
O


ATOM
716
N
VAL
A
270
17.901
−47.184
−7.951
1.00
74.60
N


ATOM
717
CA
VAL
A
270
18.065
−47.707
−6.618
1.00
74.06
C


ATOM
719
CB
VAL
A
270
17.386
−49.071
−6.519
1.00
74.08
C


ATOM
721
CG1
VAL
A
270
17.506
−49.636
−5.112
1.00
73.80
C


ATOM
725
CG2
VAL
A
270
15.916
−48.931
−6.941
1.00
73.96
C


ATOM
729
C
VAL
A
270
19.533
−47.795
−6.242
1.00
73.65
C


ATOM
730
O
VAL
A
270
19.902
−47.530
−5.094
1.00
73.33
O


ATOM
732
N
GLU
A
271
20.372
−48.138
−7.215
1.00
73.37
N


ATOM
733
CA
GLU
A
271
21.817
−48.217
−6.979
1.00
73.17
C


ATOM
735
CB
GLU
A
271
22.561
−48.776
−8.217
1.00
73.98
C


ATOM
738
CG
GLU
A
271
22.796
−50.337
−8.159
1.00
76.01
C


ATOM
741
CD
GLU
A
271
22.609
−51.064
−9.508
1.00
78.36
C


ATOM
742
OE1
GLU
A
271
23.243
−50.659
−10.516
1.00
79.71
O


ATOM
743
OE2
GLU
A
271
21.836
−52.057
−9.547
1.00
79.28
O


ATOM
744
C
GLU
A
271
22.366
−46.865
−6.532
1.00
71.90
C


ATOM
745
O
GLU
A
271
23.255
−46.796
−5.690
1.00
72.40
O


ATOM
747
N
THR
A
272
21.807
−45.787
−7.059
1.00
70.36
N


ATOM
748
CA
THR
A
272
22.149
−44.454
−6.577
1.00
69.00
C


ATOM
750
CB
THR
A
272
21.452
−43.386
−7.409
1.00
69.38
C


ATOM
752
OG1
THR
A
272
22.034
−43.392
−8.715
1.00
70.35
O


ATOM
754
CG2
THR
A
272
21.588
−41.981
−6.777
1.00
69.58
C


ATOM
758
C
THR
A
272
21.763
−44.282
−5.127
1.00
67.28
C


ATOM
759
O
THR
A
272
22.593
−43.917
−4.290
1.00
67.23
O


ATOM
761
N
GLU
A
273
20.501
−44.552
−4.829
1.00
65.42
N


ATOM
762
CA
GLU
A
273
20.027
−44.464
−3.458
1.00
63.93
C


ATOM
764
CB
GLU
A
273
18.591
−44.968
−3.371
1.00
63.50
C


ATOM
767
CG
GLU
A
273
18.019
−45.028
−1.952
1.00
62.42
C


ATOM
770
CD
GLU
A
273
16.539
−45.382
−1.938
1.00
61.38
C


ATOM
771
OE1
GLU
A
273
16.052
−45.912
−2.978
1.00
59.63
O


ATOM
772
OE2
GLU
A
273
15.868
−45.140
−0.896
1.00
57.75
O


ATOM
773
C
GLU
A
273
20.953
−45.230
−2.508
1.00
63.40
C


ATOM
774
O
GLU
A
273
21.333
−44.713
−1.464
1.00
62.38
O


ATOM
776
N
ILE
A
274
21.342
−46.444
−2.889
1.00
63.37
N


ATOM
777
CA
ILE
A
274
22.251
−47.250
−2.062
1.00
63.54
C


ATOM
779
CB
ILE
A
274
22.630
−48.611
−2.745
1.00
63.67
C


ATOM
781
CG1
ILE
A
274
21.392
−49.497
−2.987
1.00
63.32
C


ATOM
784
CD1
ILE
A
274
20.383
−49.462
−1.872
1.00
62.22
C


ATOM
788
CG2
ILE
A
274
23.663
−49.370
−1.911
1.00
62.45
C


ATOM
792
C
ILE
A
274
23.540
−46.495
−1.784
1.00
64.08
C


ATOM
793
O
ILE
A
274
23.951
−46.333
−0.625
1.00
63.61
O


ATOM
795
N
GLU
A
275
24.168
−46.033
−2.863
1.00
64.88
N


ATOM
796
CA
GLU
A
275
25.462
−45.362
−2.781
1.00
65.81
C


ATOM
798
CB
GLU
A
275
26.015
−45.089
−4.187
1.00
66.49
C


ATOM
801
CG
GLU
A
275
26.363
−46.376
−4.970
1.00
69.87
C


ATOM
804
CD
GLU
A
275
26.091
−46.258
−6.478
1.00
74.80
C


ATOM
805
OE1
GLU
A
275
26.212
−45.130
−7.013
1.00
76.85
O


ATOM
806
OE2
GLU
A
275
25.749
−47.294
−7.127
1.00
78.18
O


ATOM
807
C
GLU
A
275
25.367
−44.076
−1.972
1.00
65.43
C


ATOM
808
O
GLU
A
275
26.289
−43.746
−1.239
1.00
65.64
O


ATOM
810
N
ILE
A
276
24.259
−43.351
−2.095
1.00
65.27
N


ATOM
811
CA
ILE
A
276
24.026
−42.199
−1.229
1.00
65.16
C


ATOM
813
CB
ILE
A
276
22.697
−41.507
−1.541
1.00
65.40
C


ATOM
815
CG1
ILE
A
276
22.788
−40.726
−2.854
1.00
65.41
C


ATOM
818
CD1
ILE
A
276
21.499
−40.006
−3.215
1.00
64.13
C


ATOM
822
CG2
ILE
A
276
22.306
−40.574
−0.400
1.00
65.41
C


ATOM
826
C
ILE
A
276
24.002
−42.637
0.232
1.00
64.98
C


ATOM
827
O
ILE
A
276
24.780
−42.145
1.055
1.00
65.02
O


ATOM
829
N
LEU
A
277
23.122
−43.580
0.549
1.00
64.76
N


ATOM
830
CA
LEU
A
277
22.981
−44.039
1.923
1.00
64.96
C


ATOM
832
CB
LEU
A
277
21.860
−45.070
2.027
1.00
65.20
C


ATOM
835
CG
LEU
A
277
20.460
−44.531
1.732
1.00
65.79
C


ATOM
837
CD1
LEU
A
277
19.416
−45.537
2.209
1.00
66.56
C


ATOM
841
CD2
LEU
A
277
20.245
−43.150
2.382
1.00
66.41
C


ATOM
845
C
LEU
A
277
24.268
−44.609
2.518
1.00
65.06
C


ATOM
846
O
LEU
A
277
24.511
−44.483
3.714
1.00
64.79
O


ATOM
848
N
LYS
A
278
25.100
−45.235
1.697
1.00
65.16
N


ATOM
849
CA
LYS
A
278
26.378
−45.713
2.201
1.00
65.51
C


ATOM
851
CB
LYS
A
278
27.030
−46.697
1.214
1.00
65.65
C


ATOM
854
CG
LYS
A
278
26.365
−48.109
1.171
1.00
67.14
C


ATOM
857
CD
LYS
A
278
26.585
−48.949
2.488
1.00
68.52
C


ATOM
860
CE
LYS
A
278
26.232
−50.472
2.313
1.00
69.53
C


ATOM
863
NZ
LYS
A
278
25.883
−51.207
3.589
1.00
66.93
N


ATOM
867
C
LYS
A
278
27.319
−44.545
2.567
1.00
65.52
C


ATOM
868
O
LYS
A
278
28.085
−44.654
3.517
1.00
65.55
O


ATOM
870
N
LYS
A
279
27.249
−43.424
1.849
1.00
65.49
N


ATOM
871
CA
LYS
A
279
28.157
−42.293
2.130
1.00
65.64
C


ATOM
873
CB
LYS
A
279
28.318
−41.389
0.895
1.00
66.19
C


ATOM
876
CG
LYS
A
279
29.099
−42.051
−0.270
1.00
68.19
C


ATOM
879
CD
LYS
A
279
29.383
−41.078
−1.440
1.00
70.45
C


ATOM
882
CE
LYS
A
279
29.501
−41.815
−2.797
1.00
71.15
C


ATOM
885
NZ
LYS
A
279
28.167
−42.023
−3.483
1.00
72.27
N


ATOM
889
C
LYS
A
279
27.691
−41.456
3.323
1.00
64.79
C


ATOM
890
O
LYS
A
279
28.497
−41.012
4.133
1.00
64.19
O


ATOM
892
N
LEU
A
280
26.379
−41.254
3.425
1.00
64.20
N


ATOM
893
CA
LEU
A
280
25.805
−40.404
4.484
1.00
63.37
C


ATOM
895
CB
LEU
A
280
24.319
−40.122
4.228
1.00
63.30
C


ATOM
898
CG
LEU
A
280
23.939
−39.537
2.870
1.00
63.06
C


ATOM
900
CD1
LEU
A
280
22.442
−39.301
2.842
1.00
61.64
C


ATOM
904
CD2
LEU
A
280
24.748
−38.267
2.571
1.00
63.81
C


ATOM
908
C
LEU
A
280
25.926
−41.019
5.872
1.00
62.45
C


ATOM
909
O
LEU
A
280
25.796
−42.239
6.056
1.00
62.82
O


ATOM
911
N
ASN
A
281
26.109
−40.154
6.854
1.00
60.97
N


ATOM
912
CA
ASN
A
281
26.350
−40.604
8.197
1.00
60.17
C


ATOM
914
CB
ASN
A
281
27.850
−40.848
8.373
1.00
60.71
C


ATOM
917
CG
ASN
A
281
28.191
−41.332
9.749
1.00
60.94
C


ATOM
918
OD1
ASN
A
281
27.373
−41.980
10.418
1.00
62.72
O


ATOM
919
ND2
ASN
A
281
29.392
−41.012
10.194
1.00
61.44
N


ATOM
922
C
ASN
A
281
25.862
−39.583
9.193
1.00
58.60
C


ATOM
923
O
ASN
A
281
26.612
−38.710
9.617
1.00
58.84
O


ATOM
925
N
HIS
A
282
24.593
−39.687
9.555
1.00
56.95
N


ATOM
926
CA
HIS
A
282
23.970
−38.698
10.418
1.00
55.47
C


ATOM
928
CB
HIS
A
282
23.331
−37.594
9.563
1.00
55.48
C


ATOM
931
CG
HIS
A
282
22.928
−36.374
10.335
1.00
54.30
C


ATOM
932
ND1
HIS
A
282
21.685
−36.236
10.907
1.00
53.37
N


ATOM
934
CE1
HIS
A
282
21.613
−35.066
11.522
1.00
54.59
C


ATOM
936
NE2
HIS
A
282
22.765
−34.439
11.367
1.00
52.80
N


ATOM
938
CD2
HIS
A
282
23.598
−35.231
10.615
1.00
54.22
C


ATOM
940
C
HIS
A
282
22.928
−39.367
11.302
1.00
54.79
C


ATOM
941
O
HIS
A
282
22.216
−40.251
10.864
1.00
53.78
O


ATOM
943
N
PRO
A
283
22.821
−38.923
12.561
1.00
55.22
N


ATOM
944
CA
PRO
A
283
21.868
−39.558
13.475
1.00
55.16
C


ATOM
946
CB
PRO
A
283
22.078
−38.796
14.776
1.00
55.49
C


ATOM
949
CG
PRO
A
283
22.753
−37.516
14.383
1.00
55.31
C


ATOM
952
CD
PRO
A
283
23.591
−37.853
13.227
1.00
54.79
C


ATOM
955
C
PRO
A
283
20.405
−39.481
13.031
1.00
55.23
C


ATOM
956
O
PRO
A
283
19.606
−40.336
13.437
1.00
55.74
O


ATOM
957
N
CYS
A
284
20.067
−38.511
12.178
1.00
54.62
N


ATOM
958
CA
CYS
A
284
18.686
−38.345
11.704
1.00
54.42
C


ATOM
960
CB
CYS
A
284
18.241
−36.882
11.909
1.00
54.83
C


ATOM
963
SG
CYS
A
284
18.454
−36.288
13.620
1.00
53.38
S


ATOM
965
C
CYS
A
284
18.416
−38.801
10.256
1.00
53.91
C


ATOM
966
O
CYS
A
284
17.399
−38.446
9.669
1.00
52.91
O


ATOM
968
N
ILE
A
285
19.316
−39.600
9.698
1.00
53.94
N


ATOM
969
CA
ILE
A
285
19.091
−40.232
8.405
1.00
53.88
C


ATOM
971
CB
ILE
A
285
20.065
−39.642
7.359
1.00
53.90
C


ATOM
973
CG1
ILE
A
285
19.758
−38.143
7.172
1.00
53.23
C


ATOM
976
CD1
ILE
A
285
20.760
−37.385
6.417
1.00
51.89
C


ATOM
980
CG2
ILE
A
285
19.981
−40.427
6.039
1.00
51.62
C


ATOM
984
C
ILE
A
285
19.329
−41.726
8.585
1.00
54.47
C


ATOM
985
O
ILE
A
285
20.377
−42.097
9.092
1.00
54.41
O


ATOM
987
N
ILE
A
286
18.382
−42.588
8.205
1.00
55.22
N


ATOM
988
CA
ILE
A
286
18.606
−44.052
8.391
1.00
55.88
C


ATOM
990
CB
ILE
A
286
17.502
−45.023
7.853
1.00
55.96
C


ATOM
992
CG1
ILE
A
286
16.816
−44.464
6.615
1.00
56.03
C


ATOM
995
CD1
ILE
A
286
17.769
−44.228
5.470
1.00
56.00
C


ATOM
999
CG2
ILE
A
286
16.529
−45.444
8.959
1.00
56.11
C


ATOM
1003
C
ILE
A
286
19.861
−44.510
7.695
1.00
56.02
C


ATOM
1004
O
ILE
A
286
20.241
−43.967
6.665
1.00
56.13
O


ATOM
1006
N
LYS
A
287
20.473
−45.540
8.269
1.00
56.44
N


ATOM
1007
CA
LYS
A
287
21.625
−46.194
7.684
1.00
56.19
C


ATOM
1009
CB
LYS
A
287
22.681
−46.436
8.757
1.00
56.54
C


ATOM
1012
CG
LYS
A
287
23.626
−45.250
8.958
1.00
56.84
C


ATOM
1015
CD
LYS
A
287
23.902
−44.958
10.436
1.00
58.07
C


ATOM
1018
CE
LYS
A
287
24.607
−43.580
10.593
1.00
58.98
C


ATOM
1021
NZ
LYS
A
287
24.099
−42.824
11.759
1.00
57.94
N


ATOM
1025
C
LYS
A
287
21.184
−47.501
7.053
1.00
56.10
C


ATOM
1026
O
LYS
A
287
20.240
−48.148
7.516
1.00
56.40
O


ATOM
1028
N
ILE
A
288
21.856
−47.867
5.972
1.00
55.95
N


ATOM
1029
CA
ILE
A
288
21.597
−49.123
5.286
1.00
55.64
C


ATOM
1031
CB
ILE
A
288
21.819
−48.977
3.778
1.00
55.51
C


ATOM
1033
CG1
ILE
A
288
21.792
−50.342
3.082
1.00
54.98
C


ATOM
1036
CD1
ILE
A
288
21.897
−50.242
1.600
1.00
53.83
C


ATOM
1040
CG2
ILE
A
288
23.149
−48.309
3.511
1.00
55.89
C


ATOM
1044
C
ILE
A
288
22.539
−50.168
5.873
1.00
55.72
C


ATOM
1045
O
ILE
A
288
23.715
−49.917
6.004
1.00
55.45
O


ATOM
1047
N
LYS
A
289
22.014
−51.331
6.246
1.00
56.07
N


ATOM
1048
CA
LYS
A
289
22.824
−52.388
6.864
1.00
56.14
C


ATOM
1050
CB
LYS
A
289
22.047
−53.062
8.005
1.00
56.24
C


ATOM
1053
CG
LYS
A
289
21.971
−52.208
9.272
1.00
57.32
C


ATOM
1056
CD
LYS
A
289
21.032
−52.788
10.326
1.00
59.72
C


ATOM
1059
CE
LYS
A
289
21.619
−54.041
11.035
1.00
61.28
C


ATOM
1062
NZ
LYS
A
289
22.683
−53.752
12.070
1.00
61.20
N


ATOM
1066
C
LYS
A
289
23.261
−53.408
5.830
1.00
56.18
C


ATOM
1067
O
LYS
A
289
24.289
−54.012
5.968
1.00
56.47
O


ATOM
1069
N
ASN
A
290
22.476
−53.587
4.783
1.00
56.61
N


ATOM
1070
CA
ASN
A
290
22.771
−54.570
3.768
1.00
56.87
C


ATOM
1072
CB
ASN
A
290
22.583
−55.986
4.341
1.00
57.09
C


ATOM
1075
CG
ASN
A
290
23.464
−57.027
3.661
1.00
56.76
C


ATOM
1076
OD1
ASN
A
290
23.904
−56.838
2.531
1.00
56.75
O


ATOM
1077
ND2
ASN
A
290
23.703
−58.140
4.346
1.00
55.84
N


ATOM
1080
C
ASN
A
290
21.857
−54.370
2.557
1.00
57.22
C


ATOM
1081
O
ASN
A
290
20.869
−53.641
2.633
1.00
56.77
O


ATOM
1083
N
PHE
A
291
22.173
−55.045
1.457
1.00
58.14
N


ATOM
1084
CA
PHE
A
291
21.460
−54.844
0.206
1.00
58.77
C


ATOM
1086
CB
PHE
A
291
22.100
−53.682
−0.529
1.00
58.89
C


ATOM
1089
CG
PHE
A
291
21.480
−53.404
−1.860
1.00
60.09
C


ATOM
1090
CD1
PHE
A
291
20.144
−53.011
−1.950
1.00
60.98
C


ATOM
1092
CE1
PHE
A
291
19.545
−52.745
−3.181
1.00
61.25
C


ATOM
1094
CZ
PHE
A
291
20.285
−52.860
−4.344
1.00
62.75
C


ATOM
1096
CE2
PHE
A
291
21.635
−53.244
−4.271
1.00
63.59
C


ATOM
1098
CD2
PHE
A
291
22.223
−53.516
−3.024
1.00
62.17
C


ATOM
1100
C
PHE
A
291
21.488
−56.065
−0.692
1.00
59.06
C


ATOM
1101
O
PHE
A
291
22.520
−56.703
−0.849
1.00
58.99
O


ATOM
1103
N
PHE
A
292
20.352
−56.382
−1.297
1.00
59.94
N


ATOM
1104
CA
PHE
A
292
20.266
−57.525
−2.211
1.00
60.65
C


ATOM
1106
CB
PHE
A
292
19.630
−58.746
−1.533
1.00
60.43
C


ATOM
1109
CG
PHE
A
292
20.347
−59.179
−0.290
1.00
58.34
C


ATOM
1110
CD1
PHE
A
292
19.956
−58.690
0.955
1.00
54.84
C


ATOM
1112
CE1
PHE
A
292
20.642
−59.069
2.107
1.00
55.59
C


ATOM
1114
CZ
PHE
A
292
21.745
−59.955
2.014
1.00
54.34
C


ATOM
1116
CE2
PHE
A
292
22.127
−60.442
0.776
1.00
54.43
C


ATOM
1118
CD2
PHE
A
292
21.436
−60.053
−0.367
1.00
55.22
C


ATOM
1120
C
PHE
A
292
19.464
−57.157
−3.438
1.00
62.08
C


ATOM
1121
O
PHE
A
292
18.294
−56.819
−3.346
1.00
62.08
O


ATOM
1123
N
ASP
A
293
20.128
−57.245
−4.584
1.00
64.11
N


ATOM
1124
CA
ASP
A
293
19.556
−56.986
−5.897
1.00
65.31
C


ATOM
1126
CB
ASP
A
293
20.543
−56.117
−6.706
1.00
65.60
C


ATOM
1129
CG
ASP
A
293
20.204
−56.027
−8.189
1.00
66.04
C


ATOM
1130
OD1
ASP
A
293
19.004
−56.033
−8.556
1.00
67.97
O


ATOM
1131
OD2
ASP
A
293
21.154
−55.927
−8.987
1.00
67.09
O


ATOM
1132
C
ASP
A
293
19.353
−58.334
−6.565
1.00
66.19
C


ATOM
1133
O
ASP
A
293
20.315
−58.958
−7.018
1.00
65.94
O


ATOM
1135
N
ALA
A
294
18.097
−58.768
−6.614
1.00
67.46
N


ATOM
1136
CA
ALA
A
294
17.723
−60.069
−7.164
1.00
68.36
C


ATOM
1138
CB
ALA
A
294
17.543
−61.070
−6.026
1.00
68.32
C


ATOM
1142
C
ALA
A
294
16.435
−59.897
−7.970
1.00
69.19
C


ATOM
1143
O
ALA
A
294
16.266
−58.885
−8.641
1.00
69.35
O


ATOM
1145
N
GLU
A
295
15.514
−60.853
−7.901
1.00
70.28
N


ATOM
1146
CA
GLU
A
295
14.225
−60.702
−8.586
1.00
71.17
C


ATOM
1148
CB
GLU
A
295
13.219
−61.762
−8.111
1.00
71.91
C


ATOM
1151
CG
GLU
A
295
13.583
−63.241
−8.397
1.00
73.91
C


ATOM
1154
CD
GLU
A
295
13.519
−63.596
−9.879
1.00
77.38
C


ATOM
1155
OE1
GLU
A
295
13.028
−64.707
−10.212
1.00
80.75
O


ATOM
1156
OE2
GLU
A
295
13.948
−62.766
−10.715
1.00
78.25
O


ATOM
1157
C
GLU
A
295
13.658
−59.302
−8.325
1.00
71.10
C


ATOM
1158
O
GLU
A
295
13.089
−58.667
−9.213
1.00
71.56
O


ATOM
1160
N
ASP
A
296
13.805
−58.846
−7.083
1.00
70.85
N


ATOM
1161
CA
ASP
A
296
13.545
−57.464
−6.692
1.00
70.55
C


ATOM
1163
CB
ASP
A
296
12.342
−57.394
−5.757
1.00
70.83
C


ATOM
1166
CG
ASP
A
296
11.108
−58.023
−6.357
1.00
73.35
C


ATOM
1167
OD1
ASP
A
296
11.246
−58.783
−7.348
1.00
75.95
O


ATOM
1168
OD2
ASP
A
296
9.997
−57.756
−5.843
1.00
75.01
O


ATOM
1169
C
ASP
A
296
14.775
−56.928
−5.975
1.00
69.63
C


ATOM
1170
O
ASP
A
296
15.795
−57.630
−5.872
1.00
69.58
O


ATOM
1172
N
TYR
A
297
14.683
−55.681
−5.502
1.00
68.55
N


ATOM
1173
CA
TYR
A
297
15.694
−55.093
−4.613
1.00
67.57
C


ATOM
1175
CB
TYR
A
297
15.913
−53.608
−4.922
1.00
68.20
C


ATOM
1178
CG
TYR
A
297
16.317
−53.242
−6.346
1.00
70.05
C


ATOM
1179
CD1
TYR
A
297
17.653
−53.347
−6.767
1.00
72.08
C


ATOM
1181
CE1
TYR
A
297
18.045
−52.980
−8.065
1.00
73.13
C


ATOM
1183
CZ
TYR
A
297
17.085
−52.485
−8.959
1.00
74.77
C


ATOM
1184
OH
TYR
A
297
17.460
−52.124
−10.239
1.00
77.08
O


ATOM
1186
CE2
TYR
A
297
15.746
−52.356
−8.563
1.00
73.21
C


ATOM
1188
CD2
TYR
A
297
15.373
−52.721
−7.252
1.00
71.78
C


ATOM
1190
C
TYR
A
297
15.219
−55.217
−3.166
1.00
65.65
C


ATOM
1191
O
TYR
A
297
14.023
−55.056
−2.888
1.00
65.16
O


ATOM
1193
N
TYR
A
298
16.156
−55.496
−2.256
1.00
63.96
N


ATOM
1194
CA
TYR
A
298
15.873
−55.598
−0.808
1.00
62.61
C


ATOM
1196
CB
TYR
A
298
15.963
−57.048
−0.309
1.00
62.37
C


ATOM
1199
CG
TYR
A
298
15.056
−58.009
−1.051
1.00
62.71
C


ATOM
1200
CD1
TYR
A
298
15.369
−58.429
−2.341
1.00
62.68
C


ATOM
1202
CE1
TYR
A
298
14.544
−59.312
−3.047
1.00
63.17
C


ATOM
1204
CZ
TYR
A
298
13.376
−59.790
−2.475
1.00
63.52
C


ATOM
1205
OH
TYR
A
298
12.585
−60.658
−3.217
1.00
64.14
O


ATOM
1207
CE2
TYR
A
298
13.031
−59.396
−1.184
1.00
63.13
C


ATOM
1209
CD2
TYR
A
298
13.882
−58.502
−0.472
1.00
63.61
C


ATOM
1211
C
TYR
A
298
16.896
−54.755
−0.088
1.00
61.30
C


ATOM
1212
O
TYR
A
298
18.082
−54.893
−0.339
1.00
61.05
O


ATOM
1214
N
ILE
A
299
16.443
−53.888
0.803
1.00
60.15
N


ATOM
1215
CA
ILE
A
299
17.330
−52.981
1.508
1.00
59.57
C


ATOM
1217
CB
ILE
A
299
17.015
−51.511
1.169
1.00
59.54
C


ATOM
1219
CG1
ILE
A
299
17.165
−51.269
−0.334
1.00
60.63
C


ATOM
1222
CD1
ILE
A
299
16.438
−50.057
−0.828
1.00
61.22
C


ATOM
1226
CG2
ILE
A
299
17.943
−50.578
1.917
1.00
58.97
C


ATOM
1230
C
ILE
A
299
17.139
−53.185
2.992
1.00
59.20
C


ATOM
1231
O
ILE
A
299
16.065
−52.944
3.509
1.00
58.79
O


ATOM
1233
N
VAL
A
300
18.194
−53.614
3.677
1.00
59.15
N


ATOM
1234
CA
VAL
A
300
18.140
−53.864
5.109
1.00
58.89
C


ATOM
1236
CB
VAL
A
300
19.118
−55.002
5.519
1.00
58.69
C


ATOM
1238
CG1
VAL
A
300
18.942
−55.384
6.998
1.00
57.87
C


ATOM
1242
CG2
VAL
A
300
18.907
−56.208
4.631
1.00
57.62
C


ATOM
1246
C
VAL
A
300
18.492
−52.567
5.840
1.00
59.51
C


ATOM
1247
O
VAL
A
300
19.546
−51.967
5.575
1.00
59.35
O


ATOM
1249
N
LEU
A
301
17.619
−52.147
6.757
1.00
60.01
N


ATOM
1250
CA
LEU
A
301
17.807
−50.907
7.503
1.00
60.84
C


ATOM
1252
CB
LEU
A
301
16.788
−49.869
7.061
1.00
60.86
C


ATOM
1255
CG
LEU
A
301
16.766
−49.484
5.571
1.00
61.82
C


ATOM
1257
CD1
LEU
A
301
15.345
−49.183
5.118
1.00
59.88
C


ATOM
1261
CD2
LEU
A
301
17.724
−48.296
5.246
1.00
63.88
C


ATOM
1265
C
LEU
A
301
17.647
−51.141
8.992
1.00
61.68
C


ATOM
1266
O
LEU
A
301
17.120
−52.171
9.408
1.00
61.80
O


ATOM
1268
N
GLU
A
302
18.120
−50.185
9.789
1.00
62.73
N


ATOM
1269
CA
GLU
A
302
17.807
−50.141
11.220
1.00
63.85
C


ATOM
1271
CB
GLU
A
302
18.289
−48.817
11.855
1.00
64.43
C


ATOM
1274
CG
GLU
A
302
19.770
−48.440
11.618
1.00
66.78
C


ATOM
1277
CD
GLU
A
302
20.087
−46.974
11.999
1.00
69.99
C


ATOM
1278
OE1
GLU
A
302
19.490
−46.036
11.403
1.00
71.14
O


ATOM
1279
OE2
GLU
A
302
20.956
−46.766
12.884
1.00
70.22
O


ATOM
1280
C
GLU
A
302
16.282
−50.216
11.332
1.00
63.83
C


ATOM
1281
O
GLU
A
302
15.593
−49.616
10.513
1.00
63.67
O


ATOM
1283
N
LEU
A
303
15.746
−50.948
12.308
1.00
64.09
N


ATOM
1284
CA
LEU
A
303
14.289
−50.932
12.558
1.00
64.10
C


ATOM
1286
CB
LEU
A
303
13.807
−52.194
13.277
1.00
64.15
C


ATOM
1289
CG
LEU
A
303
12.299
−52.220
13.613
1.00
64.76
C


ATOM
1291
CD1
LEU
A
303
11.425
−52.292
12.345
1.00
64.22
C


ATOM
1295
CD2
LEU
A
303
11.974
−53.372
14.548
1.00
64.56
C


ATOM
1299
C
LEU
A
303
13.944
−49.729
13.412
1.00
63.96
C


ATOM
1300
O
LEU
A
303
14.552
−49.515
14.455
1.00
64.07
O


ATOM
1302
N
MET
A
304
12.963
−48.953
12.976
1.00
64.32
N


ATOM
1303
CA
MET
A
304
12.513
−47.773
13.724
1.00
64.35
C


ATOM
1305
CB
MET
A
304
12.436
−46.519
12.839
1.00
63.90
C


ATOM
1308
CG
MET
A
304
13.748
−46.062
12.290
1.00
63.44
C


ATOM
1311
SD
MET
A
304
14.957
−45.565
13.510
1.00
62.40
S


ATOM
1312
CE
MET
A
304
14.285
−44.011
14.078
1.00
64.56
C


ATOM
1316
C
MET
A
304
11.153
−48.114
14.259
1.00
64.47
C


ATOM
1317
O
MET
A
304
10.175
−48.111
13.526
1.00
63.93
O


ATOM
1319
N
GLU
A
305
11.092
−48.395
15.547
1.00
65.30
N


ATOM
1320
CA
GLU
A
305
9.909
−49.028
16.097
1.00
66.36
C


ATOM
1322
CB
GLU
A
305
10.270
−49.749
17.397
1.00
66.97
C


ATOM
1325
CG
GLU
A
305
11.023
−51.076
17.097
1.00
69.38
C


ATOM
1328
CD
GLU
A
305
11.585
−51.748
18.339
1.00
72.88
C


ATOM
1329
OE1
GLU
A
305
12.483
−51.137
18.972
1.00
74.64
O


ATOM
1330
OE2
GLU
A
305
11.132
−52.879
18.669
1.00
73.96
O


ATOM
1331
C
GLU
A
305
8.695
−48.095
16.219
1.00
66.20
C


ATOM
1332
O
GLU
A
305
7.558
−48.556
16.166
1.00
65.92
O


ATOM
1334
N
GLY
A
306
8.937
−46.788
16.294
1.00
66.25
N


ATOM
1335
CA
GLY
A
306
7.856
−45.792
16.299
1.00
66.14
C


ATOM
1338
C
GLY
A
306
7.036
−45.695
15.017
1.00
65.68
C


ATOM
1339
O
GLY
A
306
5.951
−45.104
15.001
1.00
65.47
O


ATOM
1341
N
GLY
A
307
7.555
−46.264
13.937
1.00
65.50
N


ATOM
1342
CA
GLY
A
307
6.837
−46.275
12.661
1.00
65.37
C


ATOM
1345
C
GLY
A
307
6.941
−44.946
11.937
1.00
65.23
C


ATOM
1346
O
GLY
A
307
7.812
−44.127
12.234
1.00
64.97
O


ATOM
1348
N
GLU
A
308
6.042
−44.736
10.986
1.00
65.35
N


ATOM
1349
CA
GLU
A
308
6.033
−43.516
10.193
1.00
65.65
C


ATOM
1351
CB
GLU
A
308
5.284
−43.737
8.887
1.00
65.80
C


ATOM
1354
CG
GLU
A
308
5.854
−44.823
7.991
1.00
66.14
C


ATOM
1357
CD
GLU
A
308
4.857
−45.263
6.931
1.00
66.49
C


ATOM
1358
OE1
GLU
A
308
3.846
−44.551
6.717
1.00
67.49
O


ATOM
1359
OE2
GLU
A
308
5.082
−46.323
6.316
1.00
68.05
O


ATOM
1360
C
GLU
A
308
5.354
−42.369
10.925
1.00
65.68
C


ATOM
1361
O
GLU
A
308
4.358
−42.570
11.604
1.00
66.25
O


ATOM
1363
N
LEU
A
309
5.883
−41.167
10.739
1.00
65.55
N


ATOM
1364
CA
LEU
A
309
5.278
−39.939
11.225
1.00
65.53
C


ATOM
1366
CB
LEU
A
309
6.174
−38.765
10.839
1.00
65.33
C


ATOM
1369
CG
LEU
A
309
5.747
−37.353
11.213
1.00
64.88
C


ATOM
1371
CD1
LEU
A
309
5.621
−37.254
12.714
1.00
63.48
C


ATOM
1375
CD2
LEU
A
309
6.750
−36.321
10.675
1.00
62.86
C


ATOM
1379
C
LEU
A
309
3.878
−39.730
10.646
1.00
66.04
C


ATOM
1380
O
LEU
A
309
3.044
−39.063
11.249
1.00
66.15
O


ATOM
1382
N
PHE
A
310
3.630
−40.288
9.474
1.00
66.59
N


ATOM
1383
CA
PHE
A
310
2.324
−40.199
8.854
1.00
67.78
C


ATOM
1385
CB
PHE
A
310
2.308
−41.023
7.570
1.00
67.63
C


ATOM
1388
CG
PHE
A
310
0.985
−41.044
6.888
1.00
68.15
C


ATOM
1389
CD1
PHE
A
310
0.520
−39.922
6.232
1.00
68.67
C


ATOM
1391
CE1
PHE
A
310
−0.703
−39.929
5.589
1.00
69.05
C


ATOM
1393
CZ
PHE
A
310
−1.478
−41.067
5.608
1.00
68.84
C


ATOM
1395
CE2
PHE
A
310
−1.024
−42.195
6.267
1.00
68.74
C


ATOM
1397
CD2
PHE
A
310
0.197
−42.180
6.905
1.00
68.63
C


ATOM
1399
C
PHE
A
310
1.210
−40.675
9.797
1.00
68.67
C


ATOM
1400
O
PHE
A
310
0.242
−39.949
10.044
1.00
68.56
O


ATOM
1402
N
ASP
A
311
1.374
−41.890
10.320
1.00
69.95
N


ATOM
1403
CA
ASP
A
311
0.405
−42.523
11.228
1.00
71.01
C


ATOM
1405
CB
ASP
A
311
0.948
−43.841
11.819
1.00
71.55
C


ATOM
1408
CG
ASP
A
311
1.412
−44.843
10.751
1.00
73.42
C


ATOM
1409
OD1
ASP
A
311
0.659
−45.069
9.774
1.00
74.21
O


ATOM
1410
OD2
ASP
A
311
2.536
−45.407
10.906
1.00
76.34
O


ATOM
1411
C
ASP
A
311
0.016
−41.630
12.402
1.00
71.20
C


ATOM
1412
O
ASP
A
311
−1.096
−41.734
12.897
1.00
71.28
O


ATOM
1414
N
LYS
A
312
0.927
−40.776
12.863
1.00
71.64
N


ATOM
1415
CA
LYS
A
312
0.642
−39.925
14.018
1.00
72.10
C


ATOM
1417
CB
LYS
A
312
1.882
−39.820
14.925
1.00
72.08
C


ATOM
1420
CG
LYS
A
312
2.209
−41.186
15.603
1.00
73.58
C


ATOM
1423
CD
LYS
A
312
3.321
−41.152
16.671
1.00
75.07
C


ATOM
1426
CE
LYS
A
312
3.710
−42.598
17.121
1.00
76.74
C


ATOM
1429
NZ
LYS
A
312
5.048
−42.722
17.855
1.00
77.13
N


ATOM
1433
C
LYS
A
312
0.039
−38.558
13.649
1.00
72.39
C


ATOM
1434
O
LYS
A
312
−0.131
−37.707
14.524
1.00
72.39
O


ATOM
1436
N
VAL
A
313
−0.314
−38.356
12.375
1.00
72.79
N


ATOM
1437
CA
VAL
A
313
−1.009
−37.123
11.942
1.00
73.32
C


ATOM
1439
CB
VAL
A
313
−0.051
−36.111
11.240
1.00
73.09
C


ATOM
1441
CG1
VAL
A
313
1.144
−35.815
12.105
1.00
72.77
C


ATOM
1445
CG2
VAL
A
313
0.373
−36.619
9.870
1.00
71.98
C


ATOM
1449
C
VAL
A
313
−2.202
−37.321
10.991
1.00
74.45
C


ATOM
1450
O
VAL
A
313
−2.827
−36.339
10.591
1.00
74.43
O


ATOM
1452
N
VAL
A
314
−2.504
−38.560
10.614
1.00
75.73
N


ATOM
1453
CA
VAL
A
314
−3.651
−38.849
9.766
1.00
76.84
C


ATOM
1455
CB
VAL
A
314
−3.606
−40.301
9.252
1.00
77.14
C


ATOM
1457
CG1
VAL
A
314
−3.862
−41.282
10.403
1.00
76.34
C


ATOM
1461
CG2
VAL
A
314
−4.600
−40.494
8.093
1.00
77.06
C


ATOM
1465
C
VAL
A
314
−4.975
−38.621
10.518
1.00
77.93
C


ATOM
1466
O
VAL
A
314
−5.029
−38.702
11.754
1.00
77.76
O


ATOM
1468
N
GLY
A
315
−6.029
−38.328
9.750
1.00
79.21
N


ATOM
1469
CA
GLY
A
315
−7.370
−38.050
10.288
1.00
80.06
C


ATOM
1472
C
GLY
A
315
−7.431
−36.861
11.241
1.00
80.73
C


ATOM
1473
O
GLY
A
315
−8.006
−36.966
12.326
1.00
81.18
O


ATOM
1475
N
ASN
A
316
−6.825
−35.736
10.852
1.00
81.18
N


ATOM
1476
CA
ASN
A
316
−6.795
−34.525
11.695
1.00
81.52
C


ATOM
1478
CB
ASN
A
316
−8.189
−33.901
11.762
1.00
81.69
C


ATOM
1481
CG
ASN
A
316
−8.792
−33.705
10.385
1.00
83.03
C


ATOM
1482
OD1
ASN
A
316
−8.272
−32.929
9.577
1.00
84.21
O


ATOM
1483
ND2
ASN
A
316
−9.880
−34.428
10.097
1.00
84.79
N


ATOM
1486
C
ASN
A
316
−6.213
−34.737
13.107
1.00
81.37
C


ATOM
1487
O
ASN
A
316
−6.389
−33.901
14.011
1.00
81.11
O


ATOM
1489
N
LYS
A
317
−5.510
−35.857
13.277
1.00
81.21
N


ATOM
1490
CA
LYS
A
317
−4.805
−36.156
14.517
1.00
81.15
C


ATOM
1492
CB
LYS
A
317
−4.335
−37.622
14.520
1.00
81.28
C


ATOM
1495
CG
LYS
A
317
−4.127
−38.265
15.898
1.00
81.67
C


ATOM
1498
CD
LYS
A
317
−3.506
−39.675
15.771
1.00
81.68
C


ATOM
1501
CE
LYS
A
317
−4.494
−40.691
15.204
1.00
81.48
C


ATOM
1504
NZ
LYS
A
317
−3.933
−41.407
14.029
1.00
81.24
N


ATOM
1508
C
LYS
A
317
−3.640
−35.177
14.489
1.00
80.75
C


ATOM
1509
O
LYS
A
317
−3.103
−34.904
13.410
1.00
80.96
O


ATOM
1511
N
ARG
A
318
−3.273
−34.605
15.632
1.00
80.02
N


ATOM
1512
CA
ARG
A
318
−2.195
−33.624
15.628
1.00
79.43
C


ATOM
1514
CB
ARG
A
318
−2.698
−32.227
15.206
1.00
79.71
C


ATOM
1517
CG
ARG
A
318
−3.850
−31.632
16.010
1.00
80.36
C


ATOM
1520
CD
ARG
A
318
−3.352
−30.834
17.206
1.00
80.59
C


ATOM
1523
NE
ARG
A
318
−4.353
−29.865
17.640
1.00
81.01
N


ATOM
1525
CZ
ARG
A
318
−4.524
−28.650
17.117
1.00
81.29
C


ATOM
1526
NH1
ARG
A
318
−3.754
−28.207
16.129
1.00
80.27
N


ATOM
1529
NH2
ARG
A
318
−5.480
−27.861
17.600
1.00
82.20
N


ATOM
1532
C
ARG
A
318
−1.439
−33.597
16.940
1.00
78.57
C


ATOM
1533
O
ARG
A
318
−2.004
−33.888
17.995
1.00
79.12
O


ATOM
1535
N
LEU
A
319
−0.153
−33.245
16.838
1.00
77.05
N


ATOM
1536
CA
LEU
A
319
0.832
−33.441
17.896
1.00
75.52
C


ATOM
1538
CB
LEU
A
319
2.202
−33.746
17.274
1.00
75.70
C


ATOM
1541
CG
LEU
A
319
2.483
−35.029
16.466
1.00
75.81
C


ATOM
1543
CD1
LEU
A
319
1.258
−35.556
15.737
1.00
76.76
C


ATOM
1547
CD2
LEU
A
319
3.633
−34.803
15.472
1.00
74.78
C


ATOM
1551
C
LEU
A
319
0.980
−32.186
18.733
1.00
74.16
C


ATOM
1552
O
LEU
A
319
0.812
−31.081
18.235
1.00
74.10
O


ATOM
1554
N
LYS
A
320
1.355
−32.356
19.994
1.00
72.57
N


ATOM
1555
CA
LYS
A
320
1.634
−31.219
20.862
1.00
71.41
C


ATOM
1557
CB
LYS
A
320
2.195
−31.682
22.211
1.00
71.71
C


ATOM
1560
CG
LYS
A
320
1.325
−32.709
22.981
1.00
72.56
C


ATOM
1563
CD
LYS
A
320
1.876
−33.038
24.397
1.00
73.53
C


ATOM
1566
CE
LYS
A
320
3.413
−33.184
24.409
1.00
74.42
C


ATOM
1569
NZ
LYS
A
320
3.957
−33.974
25.563
1.00
73.81
N


ATOM
1573
C
LYS
A
320
2.659
−30.338
20.166
1.00
70.16
C


ATOM
1574
O
LYS
A
320
3.507
−30.843
19.448
1.00
70.05
O


ATOM
1576
N
GLU
A
321
2.587
−29.028
20.373
1.00
68.57
N


ATOM
1577
CA
GLU
A
321
3.498
−28.098
19.705
1.00
67.18
C


ATOM
1579
CB
GLU
A
321
3.180
−26.643
20.077
1.00
66.94
C


ATOM
1582
CG
GLU
A
321
4.245
−25.639
19.625
1.00
67.62
C


ATOM
1585
CD
GLU
A
321
3.758
−24.192
19.468
1.00
67.87
C


ATOM
1586
OE1
GLU
A
321
2.552
−23.953
19.230
1.00
68.38
O


ATOM
1587
OE2
GLU
A
321
4.614
−23.287
19.546
1.00
67.61
O


ATOM
1588
C
GLU
A
321
4.967
−28.433
20.003
1.00
66.07
C


ATOM
1589
O
GLU
A
321
5.839
−28.297
19.129
1.00
65.70
O


ATOM
1591
N
ALA
A
322
5.225
−28.877
21.232
1.00
64.58
N


ATOM
1592
CA
ALA
A
322
6.578
−29.188
21.693
1.00
63.25
C


ATOM
1594
CB
ALA
A
322
6.593
−29.380
23.215
1.00
62.92
C


ATOM
1598
C
ALA
A
322
7.110
−30.440
21.007
1.00
62.33
C


ATOM
1599
O
ALA
A
322
8.309
−30.557
20.783
1.00
61.76
O


ATOM
1601
N
THR
A
323
6.215
−31.381
20.715
1.00
61.27
N


ATOM
1602
CA
THR
A
323
6.567
−32.558
19.950
1.00
60.86
C


ATOM
1604
CB
THR
A
323
5.417
−33.571
19.903
1.00
60.91
C


ATOM
1606
OG1
THR
A
323
4.996
−33.891
21.235
1.00
61.77
O


ATOM
1608
CG2
THR
A
323
5.847
−34.843
19.185
1.00
60.69
C


ATOM
1612
C
THR
A
323
6.933
−32.137
18.525
1.00
60.40
C


ATOM
1613
O
THR
A
323
7.965
−32.561
18.002
1.00
60.46
O


ATOM
1615
N
CYS
A
324
6.092
−31.300
17.914
1.00
59.84
N


ATOM
1616
CA
CYS
A
324
6.337
−30.760
16.575
1.00
59.40
C


ATOM
1618
CB
CYS
A
324
5.315
−29.671
16.189
1.00
59.18
C


ATOM
1621
SG
CYS
A
324
3.607
−30.242
15.940
1.00
60.83
S


ATOM
1623
C
CYS
A
324
7.731
−30.162
16.506
1.00
59.02
C


ATOM
1624
O
CYS
A
324
8.444
−30.398
15.535
1.00
59.73
O


ATOM
1626
N
LYS
A
325
8.116
−29.398
17.529
1.00
57.66
N


ATOM
1627
CA
LYS
A
325
9.397
−28.735
17.526
1.00
56.89
C


ATOM
1629
CB
LYS
A
325
9.529
−27.759
18.704
1.00
56.78
C


ATOM
1632
CG
LYS
A
325
10.670
−26.757
18.533
1.00
56.87
C


ATOM
1635
CD
LYS
A
325
10.938
−25.917
19.792
1.00
57.08
C


ATOM
1638
CE
LYS
A
325
9.830
−24.878
20.034
1.00
58.00
C


ATOM
1641
NZ
LYS
A
325
10.330
−23.657
20.742
1.00
57.03
N


ATOM
1645
C
LYS
A
325
10.508
−29.763
17.574
1.00
56.36
C


ATOM
1646
O
LYS
A
325
11.402
−29.755
16.739
1.00
56.55
O


ATOM
1648
N
LEU
A
326
10.452
−30.652
18.554
1.00
55.82
N


ATOM
1649
CA
LEU
A
326
11.501
−31.642
18.729
1.00
55.11
C


ATOM
1651
CB
LEU
A
326
11.122
−32.689
19.790
1.00
54.72
C


ATOM
1654
CG
LEU
A
326
12.138
−33.839
19.963
1.00
55.43
C


ATOM
1656
CD1
LEU
A
326
13.541
−33.288
20.261
1.00
55.66
C


ATOM
1660
CD2
LEU
A
326
11.739
−34.874
21.034
1.00
55.01
C


ATOM
1664
C
LEU
A
326
11.769
−32.319
17.385
1.00
54.43
C


ATOM
1665
O
LEU
A
326
12.905
−32.395
16.943
1.00
54.95
O


ATOM
1667
N
TYR
A
327
10.716
−32.795
16.737
1.00
53.42
N


ATOM
1668
CA
TYR
A
327
10.864
−33.550
15.510
1.00
52.70
C


ATOM
1670
CB
TYR
A
327
9.533
−34.161
15.081
1.00
52.77
C


ATOM
1673
CG
TYR
A
327
8.943
−35.226
15.974
1.00
52.81
C


ATOM
1674
CD1
TYR
A
327
9.658
−35.798
17.022
1.00
52.65
C


ATOM
1676
CE1
TYR
A
327
9.097
−36.798
17.811
1.00
52.07
C


ATOM
1678
CZ
TYR
A
327
7.808
−37.228
17.543
1.00
53.30
C


ATOM
1679
OH
TYR
A
327
7.200
−38.201
18.308
1.00
54.03
O


ATOM
1681
CE2
TYR
A
327
7.091
−36.671
16.510
1.00
53.65
C


ATOM
1683
CD2
TYR
A
327
7.659
−35.688
15.731
1.00
53.59
C


ATOM
1685
C
TYR
A
327
11.349
−32.672
14.361
1.00
51.79
C


ATOM
1686
O
TYR
A
327
12.142
−33.112
13.541
1.00
52.23
O


ATOM
1688
N
PHE
A
328
10.843
−31.448
14.284
1.00
50.11
N


ATOM
1689
CA
PHE
A
328
11.142
−30.603
13.160
1.00
48.88
C


ATOM
1691
CB
PHE
A
328
10.224
−29.394
13.123
1.00
48.38
C


ATOM
1694
CG
PHE
A
328
10.307
−28.656
11.838
1.00
46.12
C


ATOM
1695
CD1
PHE
A
328
9.809
−29.226
10.684
1.00
44.74
C


ATOM
1697
CE1
PHE
A
328
9.914
−28.562
9.467
1.00
45.53
C


ATOM
1699
CZ
PHE
A
328
10.540
−27.316
9.421
1.00
45.64
C


ATOM
1701
CE2
PHE
A
328
11.052
−26.760
10.581
1.00
45.80
C


ATOM
1703
CD2
PHE
A
328
10.938
−27.430
11.768
1.00
45.48
C


ATOM
1705
C
PHE
A
328
12.585
−30.152
13.184
1.00
48.57
C


ATOM
1706
O
PHE
A
328
13.238
−30.001
12.154
1.00
48.18
O


ATOM
1708
N
TYR
A
329
13.059
−29.901
14.383
1.00
48.20
N


ATOM
1709
CA
TYR
A
329
14.447
−29.603
14.615
1.00
47.95
C


ATOM
1711
CB
TYR
A
329
14.678
−29.545
16.140
1.00
47.63
C


ATOM
1714
CG
TYR
A
329
16.094
−29.254
16.511
1.00
46.45
C


ATOM
1715
CD1
TYR
A
329
16.660
−28.025
16.208
1.00
46.71
C


ATOM
1717
CE1
TYR
A
329
17.958
−27.736
16.541
1.00
48.16
C


ATOM
1719
CZ
TYR
A
329
18.717
−28.684
17.181
1.00
49.47
C


ATOM
1720
OH
TYR
A
329
20.025
−28.398
17.498
1.00
52.55
O


ATOM
1722
CE2
TYR
A
329
18.168
−29.922
17.507
1.00
49.23
C


ATOM
1724
CD2
TYR
A
329
16.863
−30.193
17.165
1.00
46.47
C


ATOM
1726
C
TYR
A
329
15.334
−30.679
13.966
1.00
47.74
C


ATOM
1727
O
TYR
A
329
16.298
−30.368
13.272
1.00
48.59
O


ATOM
1729
N
GLN
A
330
14.995
−31.941
14.180
1.00
47.10
N


ATOM
1730
CA
GLN
A
330
15.810
−33.047
13.668
1.00
47.43
C


ATOM
1732
CB
GLN
A
330
15.374
−34.375
14.280
1.00
47.47
C


ATOM
1735
CG
GLN
A
330
15.683
−34.484
15.751
1.00
49.80
C


ATOM
1738
CD
GLN
A
330
15.045
−35.687
16.380
1.00
51.80
C


ATOM
1739
OE1
GLN
A
330
15.421
−36.832
16.095
1.00
53.09
O


ATOM
1740
NE2
GLN
A
330
14.067
−35.443
17.244
1.00
53.40
N


ATOM
1743
C
GLN
A
330
15.728
−33.155
12.150
1.00
47.41
C


ATOM
1744
O
GLN
A
330
16.737
−33.468
11.493
1.00
47.37
O


ATOM
1746
N
MET
A
331
14.532
−32.915
11.609
1.00
46.95
N


ATOM
1747
CA
MET
A
331
14.328
−32.839
10.161
1.00
47.05
C


ATOM
1749
CB
MET
A
331
12.849
−32.566
9.820
1.00
47.42
C


ATOM
1752
CG
MET
A
331
11.888
−33.737
10.108
1.00
47.36
C


ATOM
1755
SD
MET
A
331
10.161
−33.355
9.674
1.00
50.19
S


ATOM
1756
CE
MET
A
331
9.447
−33.237
11.313
1.00
50.50
C


ATOM
1760
C
MET
A
331
15.221
−31.755
9.571
1.00
46.37
C


ATOM
1761
O
MET
A
331
15.870
−31.968
8.546
1.00
47.50
O


ATOM
1763
N
LEU
A
332
15.310
−30.617
10.240
1.00
45.37
N


ATOM
1764
CA
LEU
A
332
16.112
−29.516
9.716
1.00
44.73
C


ATOM
1766
CB
LEU
A
332
15.911
−28.232
10.516
1.00
44.06
C


ATOM
1769
CG
LEU
A
332
14.635
−27.448
10.277
1.00
42.42
C


ATOM
1771
CD1
LEU
A
332
14.544
−26.320
11.314
1.00
39.75
C


ATOM
1775
CD2
LEU
A
332
14.605
−26.895
8.840
1.00
41.89
C


ATOM
1779
C
LEU
A
332
17.582
−29.891
9.739
1.00
44.97
C


ATOM
1780
O
LEU
A
332
18.315
−29.591
8.796
1.00
44.68
O


ATOM
1782
N
LEU
A
333
18.024
−30.527
10.823
1.00
45.01
N


ATOM
1783
CA
LEU
A
333
19.427
−30.947
10.903
1.00
44.72
C


ATOM
1785
CB
LEU
A
333
19.740
−31.564
12.259
1.00
44.76
C


ATOM
1788
CG
LEU
A
333
19.789
−30.627
13.473
1.00
44.99
C


ATOM
1790
CD1
LEU
A
333
19.975
−31.486
14.704
1.00
45.77
C


ATOM
1794
CD2
LEU
A
333
20.908
−29.556
13.376
1.00
42.11
C


ATOM
1798
C
LEU
A
333
19.729
−31.944
9.790
1.00
44.41
C


ATOM
1799
O
LEU
A
333
20.795
−31.875
9.162
1.00
44.99
O


ATOM
1801
N
ALA
A
334
18.769
−32.828
9.517
1.00
43.57
N


ATOM
1802
CA
ALA
A
334
18.954
−33.867
8.529
1.00
43.35
C


ATOM
1804
CB
ALA
A
334
17.841
−34.883
8.593
1.00
43.16
C


ATOM
1808
C
ALA
A
334
19.020
−33.239
7.158
1.00
43.11
C


ATOM
1809
O
ALA
A
334
19.982
−33.421
6.430
1.00
43.54
O


ATOM
1811
N
VAL
A
335
18.022
−32.447
6.818
1.00
43.17
N


ATOM
1812
CA
VAL
A
335
18.026
−31.822
5.512
1.00
42.44
C


ATOM
1814
CB
VAL
A
335
16.694
−31.143
5.219
1.00
42.60
C


ATOM
1816
CG1
VAL
A
335
16.706
−30.411
3.847
1.00
39.84
C


ATOM
1820
CG2
VAL
A
335
15.601
−32.190
5.274
1.00
40.69
C


ATOM
1824
C
VAL
A
335
19.217
−30.901
5.384
1.00
42.93
C


ATOM
1825
O
VAL
A
335
19.819
−30.838
4.318
1.00
43.83
O


ATOM
1827
N
GLN
A
336
19.585
−30.208
6.445
1.00
43.44
N


ATOM
1828
CA
GLN
A
336
20.793
−29.369
6.418
1.00
44.97
C


ATOM
1830
CB
GLN
A
336
21.067
−28.744
7.791
1.00
45.12
C


ATOM
1833
CG
GLN
A
336
22.268
−27.786
7.770
1.00
46.48
C


ATOM
1836
CD
GLN
A
336
22.574
−27.139
9.100
1.00
47.30
C


ATOM
1837
OE1
GLN
A
336
22.680
−25.917
9.185
1.00
51.31
O


ATOM
1838
NE2
GLN
A
336
22.738
−27.947
10.140
1.00
48.53
N


ATOM
1841
C
GLN
A
336
22.058
−30.142
5.998
1.00
45.82
C


ATOM
1842
O
GLN
A
336
22.819
−29.717
5.121
1.00
45.88
O


ATOM
1844
N
TYR
A
337
22.281
−31.263
6.672
1.00
46.64
N


ATOM
1845
CA
TYR
A
337
23.405
−32.145
6.377
1.00
46.89
C


ATOM
1847
CB
TYR
A
337
23.404
−33.296
7.393
1.00
47.51
C


ATOM
1850
CG
TYR
A
337
24.348
−34.435
7.078
1.00
49.20
C


ATOM
1851
CD1
TYR
A
337
25.697
−34.391
7.477
1.00
50.00
C


ATOM
1853
CE1
TYR
A
337
26.551
−35.434
7.195
1.00
48.96
C


ATOM
1855
CZ
TYR
A
337
26.064
−36.536
6.518
1.00
49.55
C


ATOM
1856
OH
TYR
A
337
26.885
−37.590
6.234
1.00
51.72
O


ATOM
1858
CE2
TYR
A
337
24.746
−36.602
6.113
1.00
49.78
C


ATOM
1860
CD2
TYR
A
337
23.894
−35.561
6.402
1.00
48.92
C


ATOM
1862
C
TYR
A
337
23.323
−32.654
4.929
1.00
46.37
C


ATOM
1863
O
TYR
A
337
24.343
−32.737
4.227
1.00
46.14
O


ATOM
1865
N
LEU
A
338
22.119
−32.965
4.463
1.00
45.26
N


ATOM
1866
CA
LEU
A
338
21.988
−33.372
3.067
1.00
45.20
C


ATOM
1868
CB
LEU
A
338
20.548
−33.740
2.722
1.00
44.79
C


ATOM
1871
CG
LEU
A
338
20.036
−35.033
3.321
1.00
43.89
C


ATOM
1873
CD1
LEU
A
338
18.720
−35.400
2.628
1.00
44.37
C


ATOM
1877
CD2
LEU
A
338
21.021
−36.192
3.178
1.00
43.52
C


ATOM
1881
C
LEU
A
338
22.514
−32.286
2.117
1.00
44.65
C


ATOM
1882
O
LEU
A
338
23.380
−32.545
1.284
1.00
45.12
O


ATOM
1884
N
HIS
A
339
22.031
−31.068
2.286
1.00
44.54
N


ATOM
1885
CA
HIS
A
339
22.437
−29.944
1.428
1.00
44.54
C


ATOM
1887
CB
HIS
A
339
21.538
−28.713
1.666
1.00
43.43
C


ATOM
1890
CG
HIS
A
339
20.090
−28.968
1.371
1.00
43.49
C


ATOM
1891
ND1
HIS
A
339
19.085
−28.093
1.723
1.00
42.10
N


ATOM
1893
CE1
HIS
A
339
17.921
−28.593
1.346
1.00
42.21
C


ATOM
1895
NE2
HIS
A
339
18.129
−29.781
0.797
1.00
41.76
N


ATOM
1897
CD2
HIS
A
339
19.476
−30.033
0.789
1.00
41.52
C


ATOM
1899
C
HIS
A
339
23.923
−29.623
1.635
1.00
45.65
C


ATOM
1900
O
HIS
A
339
24.645
−29.376
0.681
1.00
45.85
O


ATOM
1902
N
GLU
A
340
24.395
−29.678
2.873
1.00
46.76
N


ATOM
1903
CA
GLU
A
340
25.826
−29.570
3.118
1.00
47.97
C


ATOM
1905
CB
GLU
A
340
26.163
−29.806
4.612
1.00
48.13
C


ATOM
1908
CG
GLU
A
340
25.986
−28.543
5.504
1.00
50.25
C


ATOM
1911
CD
GLU
A
340
26.147
−28.794
7.025
1.00
53.30
C


ATOM
1912
OE1
GLU
A
340
26.012
−29.948
7.502
1.00
54.76
O


ATOM
1913
OE2
GLU
A
340
26.407
−27.809
7.760
1.00
57.21
O


ATOM
1914
C
GLU
A
340
26.615
−30.533
2.217
1.00
48.19
C


ATOM
1915
O
GLU
A
340
27.678
−30.166
1.747
1.00
48.82
O


ATOM
1917
N
ASN
A
341
26.071
−31.730
1.967
1.00
48.19
N


ATOM
1918
CA
ASN
A
341
26.766
−32.815
1.260
1.00
48.05
C


ATOM
1920
CB
ASN
A
341
26.556
−34.138
2.024
1.00
47.72
C


ATOM
1923
CG
ASN
A
341
27.456
−34.245
3.256
1.00
49.22
C


ATOM
1924
OD1
ASN
A
341
28.655
−34.469
3.119
1.00
53.48
O


ATOM
1925
ND2
ASN
A
341
26.892
−34.102
4.452
1.00
46.44
N


ATOM
1928
C
ASN
A
341
26.348
−32.985
−0.216
1.00
48.08
C


ATOM
1929
O
ASN
A
341
26.583
−34.049
−0.811
1.00
47.55
O


ATOM
1931
N
GLY
A
342
25.718
−31.953
−0.802
1.00
47.76
N


ATOM
1932
CA
GLY
A
342
25.279
−31.981
−2.226
1.00
46.70
C


ATOM
1935
C
GLY
A
342
24.105
−32.898
−2.562
1.00
46.21
C


ATOM
1936
O
GLY
A
342
23.933
−33.314
−3.713
1.00
45.79
O


ATOM
1938
N
ILE
A
343
23.275
−33.214
−1.578
1.00
45.51
N


ATOM
1939
CA
ILE
A
343
22.114
−34.060
−1.841
1.00
45.28
C


ATOM
1941
CB
ILE
A
343
22.108
−35.329
−0.951
1.00
44.95
C


ATOM
1943
CG1
ILE
A
343
23.410
−36.124
−1.127
1.00
46.08
C


ATOM
1946
CD1
ILE
A
343
23.671
−36.568
−2.550
1.00
46.29
C


ATOM
1950
CG2
ILE
A
343
20.892
−36.196
−1.266
1.00
42.48
C


ATOM
1954
C
ILE
A
343
20.798
−33.333
−1.596
1.00
45.36
C


ATOM
1955
O
ILE
A
343
20.587
−32.751
−0.547
1.00
45.72
O


ATOM
1957
N
ILE
A
344
19.892
−33.452
−2.546
1.00
45.73
N


ATOM
1958
CA
ILE
A
344
18.548
−32.949
−2.413
1.00
46.09
C


ATOM
1960
CB
ILE
A
344
18.190
−32.104
−3.672
1.00
46.67
C


ATOM
1962
CG1
ILE
A
344
19.145
−30.913
−3.818
1.00
47.52
C


ATOM
1965
CD1
ILE
A
344
19.073
−30.277
−5.244
1.00
49.76
C


ATOM
1969
CG2
ILE
A
344
16.759
−31.583
−3.623
1.00
46.72
C


ATOM
1973
C
ILE
A
344
17.648
−34.172
−2.309
1.00
46.07
C


ATOM
1974
O
ILE
A
344
17.776
−35.083
−3.116
1.00
46.69
O


ATOM
1976
N
HIS
A
345
16.741
−34.199
−1.340
1.00
45.43
N


ATOM
1977
CA
HIS
A
345
15.917
−35.368
−1.123
1.00
45.30
C


ATOM
1979
CB
HIS
A
345
15.318
−35.352
0.268
1.00
44.91
C


ATOM
1982
CG
HIS
A
345
14.582
−36.604
0.615
1.00
44.33
C


ATOM
1983
ND1
HIS
A
345
13.308
−36.869
0.164
1.00
44.50
N


ATOM
1985
CE1
HIS
A
345
12.899
−38.026
0.651
1.00
45.09
C


ATOM
1987
NE2
HIS
A
345
13.885
−38.551
1.356
1.00
45.83
N


ATOM
1989
CD2
HIS
A
345
14.948
−37.677
1.355
1.00
45.41
C


ATOM
1991
C
HIS
A
345
14.793
−35.511
−2.136
1.00
45.95
C


ATOM
1992
O
HIS
A
345
14.660
−36.563
−2.748
1.00
46.59
O


ATOM
1994
N
ARG
A
346
13.962
−34.475
−2.257
1.00
46.66
N


ATOM
1995
CA
ARG
A
346
12.906
−34.357
−3.267
1.00
46.99
C


ATOM
1997
CB
ARG
A
346
13.414
−34.661
−4.678
1.00
47.38
C


ATOM
2000
CG
ARG
A
346
14.596
−33.840
−5.075
1.00
50.14
C


ATOM
2003
CD
ARG
A
346
14.494
−33.335
−6.491
1.00
53.73
C


ATOM
2006
NE
ARG
A
346
14.691
−34.425
−7.423
1.00
58.00
N


ATOM
2008
CZ
ARG
A
346
13.743
−35.005
−8.166
1.00
62.37
C


ATOM
2009
NH1
ARG
A
346
12.479
−34.600
−8.139
1.00
61.80
N


ATOM
2012
NH2
ARG
A
346
14.086
−36.009
−8.977
1.00
65.64
N


ATOM
2015
C
ARG
A
346
11.686
−35.191
−3.022
1.00
47.13
C


ATOM
2016
O
ARG
A
346
10.893
−35.355
−3.909
1.00
47.86
O


ATOM
2018
N
ASP
A
347
11.499
−35.696
−1.827
1.00
47.76
N


ATOM
2019
CA
ASP
A
347
10.325
−36.498
−1.540
1.00
48.57
C


ATOM
2021
CB
ASP
A
347
10.544
−37.935
−2.059
1.00
49.46
C


ATOM
2024
CG
ASP
A
347
9.240
−38.749
−2.194
1.00
51.98
C


ATOM
2025
OD1
ASP
A
347
8.146
−38.139
−2.233
1.00
54.15
O


ATOM
2026
OD2
ASP
A
347
9.340
−40.010
−2.270
1.00
56.77
O


ATOM
2027
C
ASP
A
347
10.038
−36.491
−0.046
1.00
48.43
C


ATOM
2028
O
ASP
A
347
9.551
−37.476
0.506
1.00
48.53
O


ATOM
2030
N
LEU
A
348
10.348
−35.376
0.616
1.00
47.86
N


ATOM
2031
CA
LEU
A
348
10.079
−35.272
2.021
1.00
47.45
C


ATOM
2033
CB
LEU
A
348
10.766
−34.050
2.614
1.00
46.99
C


ATOM
2036
CG
LEU
A
348
12.279
−34.181
2.662
1.00
46.68
C


ATOM
2038
CD1
LEU
A
348
12.926
−32.905
3.181
1.00
46.29
C


ATOM
2042
CD2
LEU
A
348
12.676
−35.348
3.525
1.00
47.53
C


ATOM
2046
C
LEU
A
348
8.574
−35.241
2.226
1.00
47.57
C


ATOM
2047
O
LEU
A
348
7.890
−34.379
1.721
1.00
46.95
O


ATOM
2049
N
LYS
A
349
8.061
−36.256
2.904
1.00
49.13
N


ATOM
2050
CA
LYS
A
349
6.656
−36.294
3.361
1.00
50.29
C


ATOM
2052
CB
LYS
A
349
5.696
−36.831
2.279
1.00
50.38
C


ATOM
2055
CG
LYS
A
349
6.354
−37.661
1.193
1.00
52.63
C


ATOM
2058
CD
LYS
A
349
5.345
−38.225
0.178
1.00
56.26
C


ATOM
2061
CE
LYS
A
349
5.834
−39.602
−0.341
1.00
59.11
C


ATOM
2064
NZ
LYS
A
349
4.928
−40.241
−1.362
1.00
62.69
N


ATOM
2068
C
LYS
A
349
6.583
−37.122
4.641
1.00
50.86
C


ATOM
2069
O
LYS
A
349
7.551
−37.818
4.995
1.00
50.72
O


ATOM
2071
N
PRO
A
350
5.451
−37.041
5.363
1.00
51.63
N


ATOM
2072
CA
PRO
A
350
5.301
−37.768
6.622
1.00
52.12
C


ATOM
2074
CB
PRO
A
350
3.863
−37.478
7.001
1.00
52.29
C


ATOM
2077
CG
PRO
A
350
3.612
−36.140
6.410
1.00
51.71
C


ATOM
2080
CD
PRO
A
350
4.283
−36.200
5.095
1.00
51.56
C


ATOM
2083
C
PRO
A
350
5.561
−39.280
6.521
1.00
52.88
C


ATOM
2084
O
PRO
A
350
6.114
−39.858
7.459
1.00
52.82
O


ATOM
2085
N
GLU
A
351
5.214
−39.879
5.380
1.00
53.73
N


ATOM
2086
CA
GLU
A
351
5.533
−41.294
5.058
1.00
55.09
C


ATOM
2088
CB
GLU
A
351
5.070
−41.663
3.620
1.00
55.57
C


ATOM
2091
CG
GLU
A
351
3.568
−41.488
3.251
1.00
57.24
C


ATOM
2094
CD
GLU
A
351
3.123
−40.032
3.067
1.00
59.54
C


ATOM
2095
OE1
GLU
A
351
3.539
−39.167
3.868
1.00
61.16
O


ATOM
2096
OE2
GLU
A
351
2.320
−39.745
2.148
1.00
63.53
O


ATOM
2097
C
GLU
A
351
7.047
−41.612
5.139
1.00
55.45
C


ATOM
2098
O
GLU
A
351
7.449
−42.763
5.381
1.00
55.42
O


ATOM
2100
N
ASN
A
352
7.884
−40.599
4.903
1.00
55.39
N


ATOM
2101
CA
ASN
A
352
9.312
−40.815
4.778
1.00
55.22
C


ATOM
2103
CB
ASN
A
352
9.819
−40.172
3.486
1.00
55.15
C


ATOM
2106
CG
ASN
A
352
9.365
−40.924
2.255
1.00
56.59
C


ATOM
2107
OD1
ASN
A
352
9.265
−42.147
2.274
1.00
60.88
O


ATOM
2108
ND2
ASN
A
352
9.104
−40.208
1.173
1.00
57.72
N


ATOM
2111
C
ASN
A
352
10.055
−40.313
5.996
1.00
55.19
C


ATOM
2112
O
ASN
A
352
11.277
−40.225
5.985
1.00
55.11
O


ATOM
2114
N
VAL
A
353
9.317
−40.013
7.060
1.00
55.36
N


ATOM
2115
CA
VAL
A
353
9.919
−39.668
8.346
1.00
55.41
C


ATOM
2117
CB
VAL
A
353
9.420
−38.317
8.826
1.00
55.10
C


ATOM
2119
CG1
VAL
A
353
9.973
−38.000
10.177
1.00
54.49
C


ATOM
2123
CG2
VAL
A
353
9.776
−37.250
7.818
1.00
52.21
C


ATOM
2127
C
VAL
A
353
9.545
−40.780
9.343
1.00
56.84
C


ATOM
2128
O
VAL
A
353
8.360
−41.014
9.615
1.00
56.79
O


ATOM
2130
N
LEU
A
354
10.564
−41.486
9.844
1.00
57.94
N


ATOM
2131
CA
LEU
A
354
10.389
−42.626
10.740
1.00
58.20
C


ATOM
2133
CB
LEU
A
354
11.254
−43.796
10.267
1.00
58.09
C


ATOM
2136
CG
LEU
A
354
11.130
−44.208
8.793
1.00
58.07
C


ATOM
2138
CD1
LEU
A
354
12.216
−45.192
8.401
1.00
56.66
C


ATOM
2142
CD2
LEU
A
354
9.779
−44.803
8.504
1.00
57.80
C


ATOM
2146
C
LEU
A
354
10.779
−42.221
12.165
1.00
58.82
C


ATOM
2147
O
LEU
A
354
11.706
−41.432
12.356
1.00
57.76
O


ATOM
2149
N
LEU
A
355
10.068
−42.778
13.150
1.00
60.04
N


ATOM
2150
CA
LEU
A
355
10.321
−42.507
14.579
1.00
61.15
C


ATOM
2152
CB
LEU
A
355
9.000
−42.163
15.275
1.00
61.08
C


ATOM
2155
CG
LEU
A
355
7.998
−41.293
14.504
1.00
60.70
C


ATOM
2157
CD1
LEU
A
355
6.676
−41.105
15.265
1.00
59.30
C


ATOM
2161
CD2
LEU
A
355
8.627
−39.964
14.227
1.00
60.79
C


ATOM
2165
C
LEU
A
355
10.987
−43.722
15.273
1.00
62.23
C


ATOM
2166
O
LEU
A
355
10.646
−44.873
14.991
1.00
61.85
O


ATOM
2168
N
SER
A
356
11.914
−43.467
16.190
1.00
63.94
N


ATOM
2169
CA
SER
A
356
12.656
−44.565
16.860
1.00
65.74
C


ATOM
2171
CB
SER
A
356
13.930
−44.024
17.517
1.00
65.28
C


ATOM
2174
OG
SER
A
356
13.672
−42.802
18.170
1.00
65.64
O


ATOM
2176
C
SER
A
356
11.848
−45.405
17.884
1.00
67.21
C


ATOM
2177
O
SER
A
356
12.247
−46.528
18.232
1.00
67.34
O


ATOM
2179
N
SER
A
357
10.722
−44.877
18.358
1.00
68.95
N


ATOM
2180
CA
SER
A
357
9.895
−45.605
19.324
1.00
70.25
C


ATOM
2182
CB
SER
A
357
10.519
−45.555
20.718
1.00
70.25
C


ATOM
2185
OG
SER
A
357
10.555
−44.222
21.200
1.00
70.69
O


ATOM
2187
C
SER
A
357
8.497
−45.043
19.411
1.00
71.38
C


ATOM
2188
O
SER
A
357
8.183
−43.985
18.845
1.00
72.02
O


ATOM
2190
N
GLN
A
358
7.658
−45.761
20.140
1.00
72.38
N


ATOM
2191
CA
GLN
A
358
6.307
−45.312
20.395
1.00
73.26
C


ATOM
2193
CB
GLN
A
358
5.463
−46.497
20.830
1.00
73.92
C


ATOM
2196
CG
GLN
A
358
5.304
−47.565
19.748
1.00
75.89
C


ATOM
2199
CD
GLN
A
358
4.743
−48.882
20.296
1.00
79.35
C


ATOM
2200
OE1
GLN
A
358
4.909
−49.203
21.483
1.00
80.93
O


ATOM
2201
NE2
GLN
A
358
4.081
−49.656
19.426
1.00
80.44
N


ATOM
2204
C
GLN
A
358
6.277
−44.201
21.449
1.00
73.21
C


ATOM
2205
O
GLN
A
358
5.256
−43.550
21.628
1.00
73.00
O


ATOM
2207
N
GLU
A
359
7.397
−43.989
22.137
1.00
73.47
N


ATOM
2208
CA
GLU
A
359
7.554
−42.841
23.035
1.00
73.76
C


ATOM
2210
CB
GLU
A
359
8.937
−42.837
23.717
1.00
73.91
C


ATOM
2213
CG
GLU
A
359
9.320
−44.108
24.504
1.00
74.95
C


ATOM
2216
CD
GLU
A
359
9.252
−43.947
26.024
1.00
76.20
C


ATOM
2217
OE1
GLU
A
359
9.052
−42.810
26.506
1.00
78.04
O


ATOM
2218
OE2
GLU
A
359
9.415
−44.960
26.739
1.00
74.69
O


ATOM
2219
C
GLU
A
359
7.421
−41.560
22.207
1.00
73.60
C


ATOM
2220
O
GLU
A
359
8.036
−41.439
21.143
1.00
73.59
O


ATOM
2222
N
GLU
A
360
6.615
−40.615
22.685
1.00
73.25
N


ATOM
2223
CA
GLU
A
360
6.415
−39.359
21.969
1.00
72.64
C


ATOM
2225
CB
GLU
A
360
5.516
−38.392
22.751
1.00
73.00
C


ATOM
2228
CG
GLU
A
360
4.087
−38.311
22.229
1.00
74.60
C


ATOM
2231
CD
GLU
A
360
3.344
−37.105
22.786
1.00
77.02
C


ATOM
2232
OE1
GLU
A
360
3.048
−36.175
21.990
1.00
78.71
O


ATOM
2233
OE2
GLU
A
360
3.084
−37.076
24.018
1.00
77.12
O


ATOM
2234
C
GLU
A
360
7.750
−38.692
21.705
1.00
71.51
C


ATOM
2235
O
GLU
A
360
8.072
−38.369
20.568
1.00
71.13
O


ATOM
2237
N
ASP
A
361
8.519
−38.486
22.765
1.00
70.15
N


ATOM
2238
CA
ASP
A
361
9.815
−37.838
22.643
1.00
69.12
C


ATOM
2240
CB
ASP
A
361
10.239
−37.259
23.985
1.00
69.49
C


ATOM
2243
CG
ASP
A
361
9.383
−36.086
24.412
1.00
70.54
C


ATOM
2244
OD1
ASP
A
361
8.234
−35.980
23.909
1.00
70.30
O


ATOM
2245
OD2
ASP
A
361
9.870
−35.284
25.256
1.00
71.17
O


ATOM
2246
C
ASP
A
361
10.880
−38.815
22.186
1.00
67.73
C


ATOM
2247
O
ASP
A
361
11.473
−39.493
23.012
1.00
67.91
O


ATOM
2249
N
CYS
A
362
11.133
−38.872
20.878
1.00
66.21
N


ATOM
2250
CA
CYS
A
362
12.096
−39.828
20.310
1.00
64.77
C


ATOM
2252
CB
CYS
A
362
11.343
−41.055
19.807
1.00
64.55
C


ATOM
2255
SG
CYS
A
362
10.347
−40.709
18.412
1.00
65.24
S


ATOM
2257
C
CYS
A
362
12.989
−39.241
19.199
1.00
63.37
C


ATOM
2258
O
CYS
A
362
12.981
−38.034
18.922
1.00
63.35
O


ATOM
2260
N
LEU
A
363
13.801
−40.094
18.587
1.00
61.73
N


ATOM
2261
CA
LEU
A
363
14.628
−39.664
17.465
1.00
60.17
C


ATOM
2263
CB
LEU
A
363
15.981
−40.369
17.462
1.00
60.59
C


ATOM
2266
CG
LEU
A
363
16.924
−40.012
18.627
1.00
60.04
C


ATOM
2268
CD1
LEU
A
363
18.092
−40.973
18.651
1.00
60.86
C


ATOM
2272
CD2
LEU
A
363
17.426
−38.598
18.518
1.00
58.93
C


ATOM
2276
C
LEU
A
363
13.876
−39.957
16.194
1.00
58.54
C


ATOM
2277
O
LEU
A
363
13.199
−40.981
16.080
1.00
57.95
O


ATOM
2279
N
ILE
A
364
13.957
−39.025
15.256
1.00
56.96
N


ATOM
2280
CA
ILE
A
364
13.367
−39.228
13.948
1.00
55.82
C


ATOM
2282
CB
ILE
A
364
12.478
−38.020
13.504
1.00
55.93
C


ATOM
2284
CG1
ILE
A
364
13.325
−36.803
13.136
1.00
55.75
C


ATOM
2287
CD1
ILE
A
364
13.782
−36.806
11.649
1.00
54.84
C


ATOM
2291
CG2
ILE
A
364
11.447
−37.664
14.572
1.00
56.64
C


ATOM
2295
C
ILE
A
364
14.486
−39.483
12.950
1.00
54.64
C


ATOM
2296
O
ILE
A
364
15.589
−38.954
13.100
1.00
54.49
O


ATOM
2298
N
LYS
A
365
14.214
−40.301
11.943
1.00
53.70
N


ATOM
2299
CA
LYS
A
365
15.153
−40.484
10.841
1.00
53.25
C


ATOM
2301
CB
LYS
A
365
15.937
−41.797
10.966
1.00
53.47
C


ATOM
2304
CG
LYS
A
365
17.010
−41.765
12.076
1.00
55.49
C


ATOM
2307
CD
LYS
A
365
17.386
−43.162
12.511
1.00
58.37
C


ATOM
2310
CE
LYS
A
365
18.316
−43.166
13.731
1.00
60.12
C


ATOM
2313
NZ
LYS
A
365
19.743
−43.384
13.341
1.00
61.38
N


ATOM
2317
C
LYS
A
365
14.423
−40.396
9.510
1.00
52.19
C


ATOM
2318
O
LYS
A
365
13.307
−40.891
9.368
1.00
51.38
O


ATOM
2320
N
ILE
A
366
15.079
−39.734
8.560
1.00
51.17
N


ATOM
2321
CA
ILE
A
366
14.554
−39.500
7.238
1.00
50.59
C


ATOM
2323
CB
ILE
A
366
15.067
−38.166
6.659
1.00
50.65
C


ATOM
2325
CG1
ILE
A
366
14.193
−37.036
7.190
1.00
51.03
C


ATOM
2328
CD1
ILE
A
366
14.996
−35.956
7.812
1.00
53.52
C


ATOM
2332
CG2
ILE
A
366
14.988
−38.152
5.167
1.00
50.10
C


ATOM
2336
C
ILE
A
366
14.954
−40.632
6.349
1.00
50.00
C


ATOM
2337
O
ILE
A
366
16.087
−41.076
6.401
1.00
49.68
O


ATOM
2339
N
THR
A
367
14.008
−41.071
5.527
1.00
49.89
N


ATOM
2340
CA
THR
A
367
14.218
−42.177
4.625
1.00
50.22
C


ATOM
2342
CB
THR
A
367
13.560
−43.433
5.182
1.00
50.18
C


ATOM
2344
OG1
THR
A
367
14.126
−44.569
4.531
1.00
50.46
O


ATOM
2346
CG2
THR
A
367
12.045
−43.408
4.974
1.00
49.66
C


ATOM
2350
C
THR
A
367
13.695
−41.920
3.192
1.00
50.58
C


ATOM
2351
O
THR
A
367
13.281
−40.802
2.842
1.00
49.35
O


ATOM
2353
N
ASP
A
368
13.732
−42.983
2.388
1.00
50.89
N


ATOM
2354
CA
ASP
A
368
13.370
−42.956
0.967
1.00
51.92
C


ATOM
2356
CB
ASP
A
368
11.874
−42.694
0.752
1.00
52.48
C


ATOM
2359
CG
ASP
A
368
11.510
−42.704
−0.716
1.00
55.33
C


ATOM
2360
OD1
ASP
A
368
12.474
−42.872
−1.512
1.00
55.24
O


ATOM
2361
OD2
ASP
A
368
10.298
−42.562
−1.074
1.00
60.92
O


ATOM
2362
C
ASP
A
368
14.162
−41.954
0.137
1.00
51.49
C


ATOM
2363
O
ASP
A
368
13.661
−40.859
−0.156
1.00
51.72
O


ATOM
2365
N
PHE
A
369
15.371
−42.343
−0.262
1.00
50.73
N


ATOM
2366
CA
PHE
A
369
16.183
−41.533
−1.133
1.00
50.21
C


ATOM
2368
CB
PHE
A
369
17.614
−41.581
−0.683
1.00
49.86
C


ATOM
2371
CG
PHE
A
369
17.861
−40.801
0.570
1.00
49.46
C


ATOM
2372
CD1
PHE
A
369
17.435
−41.281
1.793
1.00
48.66
C


ATOM
2374
CE1
PHE
A
369
17.670
−40.561
2.951
1.00
47.57
C


ATOM
2376
CZ
PHE
A
369
18.327
−39.379
2.887
1.00
46.10
C


ATOM
2378
CE2
PHE
A
369
18.752
−38.896
1.673
1.00
46.74
C


ATOM
2380
CD2
PHE
A
369
18.519
−39.583
0.529
1.00
45.50
C


ATOM
2382
C
PHE
A
369
16.067
−41.907
−2.597
1.00
50.84
C


ATOM
2383
O
PHE
A
369
16.971
−41.631
−3.358
1.00
50.68
O


ATOM
2385
N
GLY
A
370
14.932
−42.483
−2.989
1.00
52.02
N


ATOM
2386
CA
GLY
A
370
14.696
−42.927
−4.356
1.00
53.43
C


ATOM
2389
C
GLY
A
370
14.709
−41.835
−5.408
1.00
55.21
C


ATOM
2390
O
GLY
A
370
15.258
−42.018
−6.502
1.00
55.92
O


ATOM
2392
N
HIS
A
371
14.117
−40.694
−5.082
1.00
56.65
N


ATOM
2393
CA
HIS
A
371
14.025
−39.583
−6.012
1.00
57.75
C


ATOM
2395
CB
HIS
A
371
12.698
−38.847
−5.837
1.00
58.16
C


ATOM
2398
CG
HIS
A
371
11.494
−39.716
−5.973
1.00
61.57
C


ATOM
2399
ND1
HIS
A
371
10.566
−39.543
−6.978
1.00
64.03
N


ATOM
2401
CE1
HIS
A
371
9.616
−40.449
−6.850
1.00
65.75
C


ATOM
2403
NE2
HIS
A
371
9.880
−41.188
−5.787
1.00
65.34
N


ATOM
2405
CD2
HIS
A
371
11.051
−40.751
−5.220
1.00
64.54
C


ATOM
2407
C
HIS
A
371
15.121
−38.561
−5.777
1.00
57.99
C


ATOM
2408
O
HIS
A
371
15.074
−37.491
−6.346
1.00
57.95
O


ATOM
2410
N
SER
A
372
16.098
−38.837
−4.934
1.00
58.63
N


ATOM
2411
CA
SER
A
372
17.002
−37.750
−4.576
1.00
59.64
C


ATOM
2413
CB
SER
A
372
17.718
−38.025
−3.254
1.00
59.50
C


ATOM
2416
OG
SER
A
372
18.297
−39.298
−3.242
1.00
60.20
O


ATOM
2418
C
SER
A
372
17.960
−37.436
−5.720
1.00
60.37
C


ATOM
2419
O
SER
A
372
17.992
−38.140
−6.702
1.00
61.25
O


ATOM
2421
N
LYS
A
373
18.696
−36.344
−5.623
1.00
61.74
N


ATOM
2422
CA
LYS
A
373
19.573
−35.919
−6.704
1.00
63.04
C


ATOM
2424
CB
LYS
A
373
18.934
−34.783
−7.517
1.00
63.54
C


ATOM
2427
CG
LYS
A
373
18.001
−35.241
−8.654
1.00
66.39
C


ATOM
2430
CD
LYS
A
373
17.311
−34.015
−9.351
1.00
69.30
C


ATOM
2433
CE
LYS
A
373
16.399
−34.401
−10.563
1.00
69.79
C


ATOM
2436
NZ
LYS
A
373
16.972
−33.950
−11.891
1.00
68.96
N


ATOM
2440
C
LYS
A
373
20.864
−35.432
−6.115
1.00
63.56
C


ATOM
2441
O
LYS
A
373
20.882
−34.934
−4.997
1.00
63.29
O


ATOM
2443
N
ILE
A
374
21.939
−35.559
−6.879
1.00
64.99
N


ATOM
2444
CA
ILE
A
374
23.238
−35.068
−6.454
1.00
66.47
C


ATOM
2446
CB
ILE
A
374
24.357
−36.079
−6.742
1.00
66.34
C


ATOM
2448
CG1
ILE
A
374
23.940
−37.481
−6.280
1.00
66.90
C


ATOM
2451
CD1
ILE
A
374
24.946
−38.601
−6.609
1.00
67.97
C


ATOM
2455
CG2
ILE
A
374
25.627
−35.644
−6.039
1.00
65.93
C


ATOM
2459
C
ILE
A
374
23.536
−33.749
−7.155
1.00
67.83
C


ATOM
2460
O
ILE
A
374
23.488
−33.675
−8.381
1.00
68.04
O


ATOM
2462
N
LEU
A
375
23.791
−32.700
−6.378
1.00
69.39
N


ATOM
2463
CA
LEU
A
375
24.337
−31.478
−6.945
1.00
70.74
C


ATOM
2465
CB
LEU
A
375
24.391
−30.346
−5.933
1.00
70.59
C


ATOM
2468
CG
LEU
A
375
23.052
−29.802
−5.468
1.00
70.20
C


ATOM
2470
CD1
LEU
A
375
21.998
−30.183
−6.481
1.00
68.60
C


ATOM
2474
CD2
LEU
A
375
22.712
−30.300
−4.067
1.00
68.62
C


ATOM
2478
C
LEU
A
375
25.742
−31.792
−7.382
1.00
72.23
C


ATOM
2479
O
LEU
A
375
26.467
−32.505
−6.679
1.00
72.51
O


ATOM
2481
N
GLY
A
376
26.105
−31.259
−8.545
1.00
73.89
N


ATOM
2482
CA
GLY
A
376
27.417
−31.470
−9.164
1.00
74.95
C


ATOM
2485
C
GLY
A
376
27.555
−30.547
−10.372
1.00
76.05
C


ATOM
2486
O
GLY
A
376
26.622
−29.771
−10.668
1.00
76.67
O


ATOM
2488
N
GLU
A
377
28.700
−30.622
−11.067
1.00
76.87
N


ATOM
2489
CA
GLU
A
377
28.968
−29.735
−12.212
1.00
77.36
C


ATOM
2491
CB
GLU
A
377
30.291
−30.049
−12.943
1.00
77.88
C


ATOM
2494
CG
GLU
A
377
30.512
−29.183
−14.222
1.00
79.59
C


ATOM
2497
CD
GLU
A
377
31.992
−29.047
−14.664
1.00
81.28
C


ATOM
2498
OE1
GLU
A
377
32.569
−30.016
−15.226
1.00
81.70
O


ATOM
2499
OE2
GLU
A
377
32.559
−27.943
−14.475
1.00
82.09
O


ATOM
2500
C
GLU
A
377
27.797
−29.800
−13.179
1.00
76.82
C


ATOM
2501
O
GLU
A
377
27.482
−30.849
−13.733
1.00
77.21
O


ATOM
2503
N
THR
A
378
27.136
−28.663
−13.325
1.00
76.13
N


ATOM
2504
CA
THR
A
378
25.991
−28.543
−14.178
1.00
75.58
C


ATOM
2506
CB
THR
A
378
25.173
−27.325
−13.747
1.00
75.78
C


ATOM
2508
OG1
THR
A
378
26.057
−26.201
−13.640
1.00
75.38
O


ATOM
2510
CG2
THR
A
378
24.495
−27.573
−12.381
1.00
74.99
C


ATOM
2514
C
THR
A
378
26.512
−28.345
−15.593
1.00
75.09
C


ATOM
2515
O
THR
A
378
27.664
−27.905
−15.791
1.00
74.86
O


ATOM
2517
N
SER
A
379
25.693
−28.707
−16.576
1.00
74.28
N


ATOM
2518
CA
SER
A
379
26.000
−28.328
−17.947
1.00
74.12
C


ATOM
2520
CB
SER
A
379
25.151
−29.082
−19.000
1.00
74.08
C


ATOM
2523
OG
SER
A
379
23.824
−29.353
−18.587
1.00
73.75
O


ATOM
2525
C
SER
A
379
25.891
−26.804
−18.101
1.00
73.69
C


ATOM
2526
O
SER
A
379
26.483
−26.243
−19.013
1.00
73.69
O


ATOM
2528
N
LEU
A
380
25.165
−26.145
−17.194
1.00
73.30
N


ATOM
2529
CA
LEU
A
380
25.072
−24.688
−17.190
1.00
72.81
C


ATOM
2531
CB
LEU
A
380
24.083
−24.171
−16.130
1.00
72.30
C


ATOM
2534
CG
LEU
A
380
23.642
−22.704
−16.313
1.00
71.47
C


ATOM
2536
CD1
LEU
A
380
22.887
−22.548
−17.610
1.00
70.50
C


ATOM
2540
CD2
LEU
A
380
22.792
−22.164
−15.164
1.00
68.86
C


ATOM
2544
C
LEU
A
380
26.447
−24.097
−16.960
1.00
73.16
C


ATOM
2545
O
LEU
A
380
26.861
−23.210
−17.691
1.00
73.06
O


ATOM
2547
N
MET
A
381
27.165
−24.602
−15.961
1.00
73.70
N


ATOM
2548
CA
MET
A
381
28.493
−24.075
−15.650
1.00
74.08
C


ATOM
2550
CB
MET
A
381
29.094
−24.784
−14.418
1.00
74.25
C


ATOM
2553
CG
MET
A
381
28.435
−24.360
−13.051
1.00
75.07
C


ATOM
2556
SD
MET
A
381
28.696
−25.452
−11.581
1.00
76.15
S


ATOM
2557
CE
MET
A
381
27.423
−24.933
−10.408
1.00
73.78
C


ATOM
2561
C
MET
A
381
29.393
−24.165
−16.895
1.00
74.29
C


ATOM
2562
O
MET
A
381
29.954
−23.153
−17.335
1.00
74.27
O


ATOM
2564
N
ARG
A
382
29.473
−25.352
−17.499
1.00
74.49
N


ATOM
2565
CA
ARG
A
382
30.334
−25.573
−18.674
1.00
74.86
C


ATOM
2567
CB
ARG
A
382
30.442
−27.078
−19.006
1.00
75.57
C


ATOM
2570
CG
ARG
A
382
31.717
−27.507
−19.786
1.00
78.25
C


ATOM
2573
CD
ARG
A
382
32.989
−27.432
−18.913
1.00
81.68
C


ATOM
2576
NE
ARG
A
382
34.194
−27.984
−19.558
1.00
84.37
N


ATOM
2578
CZ
ARG
A
382
34.876
−29.071
−19.161
1.00
86.53
C


ATOM
2579
NH1
ARG
A
382
34.507
−29.794
−18.095
1.00
86.72
N


ATOM
2582
NH2
ARG
A
382
35.963
−29.440
−19.836
1.00
86.11
N


ATOM
2585
C
ARG
A
382
29.845
−24.774
−19.894
1.00
74.02
C


ATOM
2586
O
ARG
A
382
30.645
−24.209
−20.644
1.00
73.32
O


ATOM
2588
N
THR
A
383
28.531
−24.717
−20.079
1.00
73.57
N


ATOM
2589
CA
THR
A
383
27.946
−23.906
−21.149
1.00
73.31
C


ATOM
2591
CB
THR
A
383
26.396
−23.916
−21.120
1.00
73.37
C


ATOM
2593
OG1
THR
A
383
25.906
−25.229
−21.432
1.00
72.99
O


ATOM
2595
CG2
THR
A
383
25.827
−22.925
−22.133
1.00
73.52
C


ATOM
2599
C
THR
A
383
28.431
−22.470
−21.047
1.00
73.06
C


ATOM
2600
O
THR
A
383
28.774
−21.875
−22.046
1.00
72.91
O


ATOM
2602
N
LEU
A
384
28.492
−21.941
−19.831
1.00
73.25
N


ATOM
2603
CA
LEU
A
384
28.885
−20.558
−19.612
1.00
73.59
C


ATOM
2605
CB
LEU
A
384
28.488
−20.089
−18.206
1.00
73.14
C


ATOM
2608
CG
LEU
A
384
27.007
−20.030
−17.841
1.00
72.28
C


ATOM
2610
CD1
LEU
A
384
26.836
−19.411
−16.459
1.00
70.01
C


ATOM
2614
CD2
LEU
A
384
26.203
−19.278
−18.890
1.00
70.90
C


ATOM
2618
C
LEU
A
384
30.380
−20.283
−19.807
1.00
74.49
C


ATOM
2619
O
LEU
A
384
30.768
−19.120
−19.924
1.00
74.87
O


ATOM
2621
N
CYS
A
385
31.232
−21.306
−19.825
1.00
75.27
N


ATOM
2622
CA
CYS
A
385
32.678
−21.043
−20.002
1.00
75.89
C


ATOM
2624
CB
CYS
A
385
33.523
−22.240
−19.584
1.00
75.95
C


ATOM
2627
SG
CYS
A
385
33.556
−22.422
−17.781
1.00
78.97
S


ATOM
2629
C
CYS
A
385
33.025
−20.590
−21.423
1.00
75.60
C


ATOM
2630
O
CYS
A
385
33.980
−19.818
−21.614
1.00
75.75
O


ATOM
2632
N
GLY
A
386
32.242
−21.046
−22.405
1.00
74.84
N


ATOM
2633
CA
GLY
A
386
32.369
−20.553
−23.782
1.00
74.47
C


ATOM
2636
C
GLY
A
386
31.617
−19.244
−23.984
1.00
73.79
C


ATOM
2637
O
GLY
A
386
30.912
−18.789
−23.086
1.00
74.13
O


ATOM
2639
N
THR
A
387
31.776
−18.626
−25.153
1.00
72.88
N


ATOM
2640
CA
THR
A
387
30.977
−17.454
−25.516
1.00
72.16
C


ATOM
2642
CB
THR
A
387
31.539
−16.676
−26.725
1.00
72.42
C


ATOM
2644
OG1
THR
A
387
32.931
−16.436
−26.536
1.00
73.70
O


ATOM
2646
CG2
THR
A
387
30.835
−15.317
−26.895
1.00
73.31
C


ATOM
2650
C
THR
A
387
29.595
−17.953
−25.897
1.00
70.89
C


ATOM
2651
O
THR
A
387
29.465
−19.043
−26.477
1.00
70.82
O


ATOM
2653
N
PRO
A
388
28.563
−17.170
−25.551
1.00
68.94
N


ATOM
2654
CA
PRO
A
388
27.199
−17.471
−25.916
1.00
67.62
C


ATOM
2656
CB
PRO
A
388
26.399
−16.892
−24.747
1.00
67.72
C


ATOM
2659
CG
PRO
A
388
27.173
−15.727
−24.336
1.00
68.59
C


ATOM
2662
CD
PRO
A
388
28.622
−16.079
−24.562
1.00
69.15
C


ATOM
2665
C
PRO
A
388
26.802
−16.837
−27.240
1.00
65.94
C


ATOM
2666
O
PRO
A
388
25.627
−16.600
−27.485
1.00
65.83
O


ATOM
2667
N
THR
A
389
27.777
−16.591
−28.105
1.00
64.11
N


ATOM
2668
CA
THR
A
389
27.483
−16.263
−29.483
1.00
62.60
C


ATOM
2670
CB
THR
A
389
28.682
−16.621
−30.394
1.00
62.45
C


ATOM
2672
OG1
THR
A
389
29.877
−16.074
−29.832
1.00
63.70
O


ATOM
2674
CG2
THR
A
389
28.507
−16.080
−31.825
1.00
61.74
C


ATOM
2678
C
THR
A
389
26.228
−17.031
−29.925
1.00
61.08
C


ATOM
2679
O
THR
A
389
25.367
−16.462
−30.603
1.00
61.74
O


ATOM
2681
N
TYR
A
390
26.133
−18.306
−29.525
1.00
58.96
N


ATOM
2682
CA
TYR
A
390
25.076
−19.220
−29.968
1.00
57.09
C


ATOM
2684
CB
TYR
A
390
25.701
−20.475
−30.591
1.00
57.06
C


ATOM
2687
CG
TYR
A
390
26.638
−20.160
−31.737
1.00
56.98
C


ATOM
2688
CD1
TYR
A
390
26.158
−20.033
−33.023
1.00
56.74
C


ATOM
2690
CE1
TYR
A
390
27.002
−19.710
−34.074
1.00
57.62
C


ATOM
2692
CZ
TYR
A
390
28.343
−19.508
−33.838
1.00
57.75
C


ATOM
2693
OH
TYR
A
390
29.149
−19.195
−34.899
1.00
60.22
O


ATOM
2695
CE2
TYR
A
390
28.864
−19.619
−32.566
1.00
56.62
C


ATOM
2697
CD2
TYR
A
390
28.009
−19.944
−31.518
1.00
58.02
C


ATOM
2699
C
TYR
A
390
24.141
−19.633
−28.846
1.00
55.58
C


ATOM
2700
O
TYR
A
390
23.200
−20.338
−29.081
1.00
56.20
O


ATOM
2702
N
LEU
A
391
24.385
−19.192
−27.629
1.00
53.40
N


ATOM
2703
CA
LEU
A
391
23.577
−19.612
−26.522
1.00
52.11
C


ATOM
2705
CB
LEU
A
391
24.285
−19.234
−25.237
1.00
52.19
C


ATOM
2708
CG
LEU
A
391
24.018
−20.128
−24.050
1.00
53.31
C


ATOM
2710
CD1
LEU
A
391
23.843
−21.619
−24.518
1.00
55.41
C


ATOM
2714
CD2
LEU
A
391
25.162
−19.948
−23.034
1.00
52.32
C


ATOM
2718
C
LEU
A
391
22.160
−19.014
−26.540
1.00
50.87
C


ATOM
2719
O
LEU
A
391
21.966
−17.842
−26.843
1.00
51.39
O


ATOM
2721
N
ALA
A
392
21.184
−19.836
−26.179
1.00
48.95
N


ATOM
2722
CA
ALA
A
392
19.777
−19.508
−26.298
1.00
46.87
C


ATOM
2724
CB
ALA
A
392
18.968
−20.781
−26.318
1.00
45.79
C


ATOM
2728
C
ALA
A
392
19.358
−18.656
−25.123
1.00
45.35
C


ATOM
2729
O
ALA
A
392
19.828
−18.877
−24.024
1.00
46.11
O


ATOM
2731
N
PRO
A
393
18.438
−17.702
−25.329
1.00
43.92
N


ATOM
2732
CA
PRO
A
393
17.952
−16.819
−24.275
1.00
42.86
C


ATOM
2734
CB
PRO
A
393
16.739
−16.141
−24.902
1.00
43.34
C


ATOM
2737
CG
PRO
A
393
16.835
−16.342
−26.360
1.00
43.91
C


ATOM
2740
CD
PRO
A
393
17.899
−17.341
−26.647
1.00
44.23
C


ATOM
2743
C
PRO
A
393
17.490
−17.531
−23.026
1.00
42.30
C


ATOM
2744
O
PRO
A
393
17.758
−17.074
−21.912
1.00
42.30
O


ATOM
2745
N
GLU
A
394
16.763
−18.627
−23.195
1.00
41.33
N


ATOM
2746
CA
GLU
A
394
16.180
−19.290
−22.038
1.00
41.04
C


ATOM
2748
CB
GLU
A
394
15.124
−20.345
−22.434
1.00
40.54
C


ATOM
2751
CG
GLU
A
394
15.568
−21.479
−23.398
1.00
41.14
C


ATOM
2754
CD
GLU
A
394
15.529
−21.104
−24.878
1.00
41.67
C


ATOM
2755
OE1
GLU
A
394
15.673
−19.896
−25.242
1.00
41.71
O


ATOM
2756
OE2
GLU
A
394
15.359
−22.034
−25.684
1.00
39.55
O


ATOM
2757
C
GLU
A
394
17.272
−19.855
−21.134
1.00
40.97
C


ATOM
2758
O
GLU
A
394
17.115
−19.925
−19.916
1.00
41.23
O


ATOM
2760
N
VAL
A
395
18.402
−20.233
−21.716
1.00
40.74
N


ATOM
2761
CA
VAL
A
395
19.458
−20.780
−20.892
1.00
40.47
C


ATOM
2763
CB
VAL
A
395
20.541
−21.513
−21.743
1.00
40.76
C


ATOM
2765
CG1
VAL
A
395
21.686
−21.977
−20.882
1.00
38.79
C


ATOM
2769
CG2
VAL
A
395
19.897
−22.713
−22.477
1.00
38.93
C


ATOM
2773
C
VAL
A
395
20.006
−19.642
−20.056
1.00
40.54
C


ATOM
2774
O
VAL
A
395
20.178
−19.778
−18.848
1.00
39.07
O


ATOM
2776
N
LEU
A
396
20.239
−18.506
−20.697
1.00
41.60
N


ATOM
2777
CA
LEU
A
396
20.714
−17.321
−19.972
1.00
42.68
C


ATOM
2779
CB
LEU
A
396
21.100
−16.202
−20.934
1.00
42.97
C


ATOM
2782
CG
LEU
A
396
22.355
−16.461
−21.802
1.00
43.25
C


ATOM
2784
CD1
LEU
A
396
22.581
−15.341
−22.806
1.00
44.53
C


ATOM
2788
CD2
LEU
A
396
23.572
−16.625
−20.966
1.00
42.41
C


ATOM
2792
C
LEU
A
396
19.713
−16.830
−18.924
1.00
43.37
C


ATOM
2793
O
LEU
A
396
20.108
−16.433
−17.833
1.00
43.85
O


ATOM
2795
N
VAL
A
397
18.421
−16.913
−19.208
1.00
44.11
N


ATOM
2796
CA
VAL
A
397
17.425
−16.518
−18.221
1.00
44.38
C


ATOM
2798
CB
VAL
A
397
15.996
−16.483
−18.832
1.00
45.56
C


ATOM
2800
CG1
VAL
A
397
14.927
−16.380
−17.737
1.00
44.34
C


ATOM
2804
CG2
VAL
A
397
15.878
−15.366
−19.898
1.00
42.24
C


ATOM
2808
C
VAL
A
397
17.430
−17.438
−17.024
1.00
45.00
C


ATOM
2809
O
VAL
A
397
17.151
−16.992
−15.919
1.00
46.57
O


ATOM
2811
N
SER
A
398
17.767
−18.705
−17.227
1.00
45.19
N


ATOM
2812
CA
SER
A
398
17.756
−19.711
−16.159
1.00
45.53
C


ATOM
2814
CB
SER
A
398
17.794
−21.116
−16.760
1.00
45.57
C


ATOM
2817
OG
SER
A
398
19.110
−21.484
−17.138
1.00
45.64
O


ATOM
2819
C
SER
A
398
18.906
−19.561
−15.173
1.00
46.68
C


ATOM
2820
O
SER
A
398
18.878
−20.094
−14.056
1.00
46.69
O


ATOM
2822
N
VAL
A
399
19.935
−18.836
−15.581
1.00
48.01
N


ATOM
2823
CA
VAL
A
399
21.034
−18.495
−14.678
1.00
48.40
C


ATOM
2825
CB
VAL
A
399
22.084
−17.637
−15.397
1.00
48.50
C


ATOM
2827
CG1
VAL
A
399
23.065
−17.003
−14.391
1.00
48.78
C


ATOM
2831
CG2
VAL
A
399
22.826
−18.493
−16.452
1.00
47.62
C


ATOM
2835
C
VAL
A
399
20.552
−17.764
−13.422
1.00
49.45
C


ATOM
2836
O
VAL
A
399
21.135
−17.929
−12.347
1.00
49.64
O


ATOM
2838
N
GLY
A
400
19.494
−16.959
−13.544
1.00
50.27
N


ATOM
2839
CA
GLY
A
400
18.987
−16.234
−12.393
1.00
50.67
C


ATOM
2842
C
GLY
A
400
18.715
−17.150
−11.211
1.00
51.33
C


ATOM
2843
O
GLY
A
400
18.957
−16.749
−10.079
1.00
52.05
O


ATOM
2845
N
THR
A
401
18.235
−18.381
−11.470
1.00
51.53
N


ATOM
2846
CA
THR
A
401
17.792
−19.308
−10.404
1.00
51.64
C


ATOM
2848
CB
THR
A
401
16.297
−19.616
−10.553
1.00
51.98
C


ATOM
2850
OG1
THR
A
401
15.998
−19.949
−11.923
1.00
53.59
O


ATOM
2852
CG2
THR
A
401
15.489
−18.370
−10.168
1.00
51.82
C


ATOM
2856
C
THR
A
401
18.563
−20.625
−10.265
1.00
51.24
C


ATOM
2857
O
THR
A
401
18.437
−21.310
−9.265
1.00
52.12
O


ATOM
2859
N
ALA
A
402
19.361
−20.999
−11.249
1.00
50.44
N


ATOM
2860
CA
ALA
A
402
20.260
−22.130
−11.088
1.00
49.38
C


ATOM
2862
CB
ALA
A
402
21.439
−22.008
−12.062
1.00
48.67
C


ATOM
2866
C
ALA
A
402
20.791
−22.202
−9.656
1.00
48.66
C


ATOM
2867
O
ALA
A
402
21.223
−21.203
−9.119
1.00
49.38
O


ATOM
2869
N
GLY
A
403
20.801
−23.387
−9.056
1.00
47.59
N


ATOM
2870
CA
GLY
A
403
21.515
−23.598
−7.795
1.00
46.67
C


ATOM
2873
C
GLY
A
403
20.621
−23.535
−6.583
1.00
46.21
C


ATOM
2874
O
GLY
A
403
21.110
−23.613
−5.456
1.00
46.21
O


ATOM
2876
N
TYR
A
404
19.310
−23.428
−6.834
1.00
45.04
N


ATOM
2877
CA
TYR
A
404
18.278
−23.380
−5.816
1.00
44.20
C


ATOM
2879
CB
TYR
A
404
17.476
−22.062
−5.936
1.00
44.30
C


ATOM
2882
CG
TYR
A
404
18.202
−20.918
−5.298
1.00
44.77
C


ATOM
2883
CD1
TYR
A
404
19.160
−20.199
−6.006
1.00
48.10
C


ATOM
2885
CE1
TYR
A
404
19.879
−19.150
−5.389
1.00
48.41
C


ATOM
2887
CZ
TYR
A
404
19.626
−18.838
−4.066
1.00
45.56
C


ATOM
2888
OH
TYR
A
404
20.322
−17.826
−3.474
1.00
47.93
O


ATOM
2890
CE2
TYR
A
404
18.679
−19.534
−3.358
1.00
44.85
C


ATOM
2892
CD2
TYR
A
404
17.981
−20.582
−3.974
1.00
44.11
C


ATOM
2894
C
TYR
A
404
17.320
−24.570
−5.882
1.00
43.74
C


ATOM
2895
O
TYR
A
404
16.239
−24.529
−5.279
1.00
43.41
O


ATOM
2897
N
ASN
A
405
17.678
−25.624
−6.607
1.00
43.18
N


ATOM
2898
CA
ASN
A
405
16.847
−26.836
−6.582
1.00
43.07
C


ATOM
2900
CB
ASN
A
405
17.487
−27.999
−7.344
1.00
43.67
C


ATOM
2903
CG
ASN
A
405
17.735
−27.701
−8.788
1.00
45.40
C


ATOM
2904
OD1
ASN
A
405
17.279
−26.709
−9.320
1.00
51.30
O


ATOM
2905
ND2
ASN
A
405
18.461
−28.586
−9.447
1.00
51.39
N


ATOM
2908
C
ASN
A
405
16.577
−27.292
−5.146
1.00
42.04
C


ATOM
2909
O
ASN
A
405
15.495
−27.770
−4.834
1.00
42.99
O


ATOM
2911
N
ARG
A
406
17.567
−27.135
−4.273
1.00
41.43
N


ATOM
2912
CA
ARG
A
406
17.444
−27.529
−2.855
1.00
40.89
C


ATOM
2914
CB
ARG
A
406
18.732
−27.231
−2.079
1.00
41.15
C


ATOM
2917
CG
ARG
A
406
18.978
−25.767
−1.673
1.00
42.83
C


ATOM
2920
CD
ARG
A
406
20.433
−25.565
−1.179
1.00
43.63
C


ATOM
2923
NE
ARG
A
406
21.356
−25.802
−2.292
1.00
47.26
N


ATOM
2925
CZ
ARG
A
406
22.688
−25.728
−2.226
1.00
47.25
C


ATOM
2926
NH1
ARG
A
406
23.319
−25.430
−1.101
1.00
46.98
N


ATOM
2929
NH2
ARG
A
406
23.389
−25.940
−3.318
1.00
47.87
N


ATOM
2932
C
ARG
A
406
16.297
−26.878
−2.120
1.00
40.15
C


ATOM
2933
O
ARG
A
406
15.797
−27.442
−1.174
1.00
40.13
O


ATOM
2935
N
ALA
A
407
15.909
−25.670
−2.523
1.00
38.94
N


ATOM
2936
CA
ALA
A
407
14.777
−25.018
−1.908
1.00
37.74
C


ATOM
2938
CB
ALA
A
407
14.538
−23.682
−2.541
1.00
35.93
C


ATOM
2942
C
ALA
A
407
13.496
−25.908
−1.931
1.00
37.54
C


ATOM
2943
O
ALA
A
407
12.646
−25.741
−1.077
1.00
37.24
O


ATOM
2945
N
VAL
A
408
13.359
−26.868
−2.852
1.00
37.48
N


ATOM
2946
CA
VAL
A
408
12.102
−27.661
−2.900
1.00
37.20
C


ATOM
2948
CB
VAL
A
408
11.996
−28.590
−4.174
1.00
37.55
C


ATOM
2950
CG1
VAL
A
408
12.259
−27.815
−5.461
1.00
35.10
C


ATOM
2954
CG2
VAL
A
408
12.964
−29.734
−4.083
1.00
36.52
C


ATOM
2958
C
VAL
A
408
11.972
−28.510
−1.645
1.00
37.77
C


ATOM
2959
O
VAL
A
408
10.874
−28.844
−1.229
1.00
38.37
O


ATOM
2961
N
ASP
A
409
13.103
−28.858
−1.036
1.00
38.23
N


ATOM
2962
CA
ASP
A
409
13.118
−29.533
0.256
1.00
38.49
C


ATOM
2964
CB
ASP
A
409
14.530
−30.022
0.586
1.00
38.54
C


ATOM
2967
CG
ASP
A
409
14.913
−31.344
−0.121
1.00
39.97
C


ATOM
2968
OD1
ASP
A
409
14.029
−32.048
−0.681
1.00
37.42
O


ATOM
2969
OD2
ASP
A
409
16.135
−31.679
−0.074
1.00
40.55
O


ATOM
2970
C
ASP
A
409
12.624
−28.618
1.385
1.00
39.12
C


ATOM
2971
O
ASP
A
409
12.028
−29.072
2.374
1.00
39.10
O


ATOM
2973
N
CYS
A
410
12.885
−27.330
1.266
1.00
39.98
N


ATOM
2974
CA
CYS
A
410
12.471
−26.412
2.320
1.00
40.84
C


ATOM
2976
CB
CYS
A
410
13.291
−25.131
2.286
1.00
41.09
C


ATOM
2979
SG
CYS
A
410
15.032
−25.442
2.851
1.00
41.18
S


ATOM
2981
C
CYS
A
410
10.974
−26.179
2.227
1.00
41.43
C


ATOM
2982
O
CYS
A
410
10.302
−26.140
3.242
1.00
41.27
O


ATOM
2984
N
TRP
A
411
10.443
−26.109
1.011
1.00
42.36
N


ATOM
2985
CA
TRP
A
411
9.009
−26.041
0.812
1.00
43.21
C


ATOM
2987
CB
TRP
A
411
8.670
−26.042
−0.674
1.00
43.89
C


ATOM
2990
CG
TRP
A
411
7.168
−25.986
−0.922
1.00
45.03
C


ATOM
2991
CD1
TRP
A
411
6.315
−27.049
−1.020
1.00
46.43
C


ATOM
2993
NE1
TRP
A
411
5.032
−26.607
−1.216
1.00
46.64
N


ATOM
2995
CE2
TRP
A
411
5.038
−25.243
−1.264
1.00
44.12
C


ATOM
2996
CD2
TRP
A
411
6.372
−24.818
−1.073
1.00
43.38
C


ATOM
2997
CE3
TRP
A
411
6.652
−23.447
−1.063
1.00
44.77
C


ATOM
2999
CZ3
TRP
A
411
5.607
−22.550
−1.266
1.00
45.34
C


ATOM
3001
CH2
TRP
A
411
4.285
−23.014
−1.455
1.00
45.72
C


ATOM
3003
CZ2
TRP
A
411
3.987
−24.353
−1.446
1.00
43.97
C


ATOM
3005
C
TRP
A
411
8.298
−27.215
1.490
1.00
43.79
C


ATOM
3006
O
TRP
A
411
7.411
−27.011
2.336
1.00
43.19
O


ATOM
3008
N
SER
A
412
8.702
−28.438
1.122
1.00
43.89
N


ATOM
3009
CA
SER
A
412
8.152
−29.657
1.744
1.00
43.75
C


ATOM
3011
CB
SER
A
412
8.868
−30.902
1.217
1.00
43.71
C


ATOM
3014
OG
SER
A
412
8.909
−30.883
−0.202
1.00
44.41
O


ATOM
3016
C
SER
A
412
8.225
−29.636
3.261
1.00
43.69
C


ATOM
3017
O
SER
A
412
7.274
−30.008
3.940
1.00
44.02
O


ATOM
3019
N
LEU
A
413
9.356
−29.227
3.824
1.00
44.18
N


ATOM
3020
CA
LEU
A
413
9.438
−29.173
5.286
1.00
44.11
C


ATOM
3022
CB
LEU
A
413
10.819
−28.740
5.754
1.00
43.89
C


ATOM
3025
CG
LEU
A
413
11.942
−29.779
5.640
1.00
44.19
C


ATOM
3027
CD1
LEU
A
413
13.296
−29.166
5.875
1.00
40.72
C


ATOM
3031
CD2
LEU
A
413
11.713
−30.950
6.603
1.00
44.60
C


ATOM
3035
C
LEU
A
413
8.371
−28.191
5.761
1.00
44.88
C


ATOM
3036
O
LEU
A
413
7.682
−28.436
6.745
1.00
45.07
O


ATOM
3038
N
GLY
A
414
8.226
−27.088
5.025
1.00
45.47
N


ATOM
3039
CA
GLY
A
414
7.165
−26.131
5.257
1.00
45.73
C


ATOM
3042
C
GLY
A
414
5.817
−26.807
5.350
1.00
46.41
C


ATOM
3043
O
GLY
A
414
5.104
−26.640
6.352
1.00
46.96
O


ATOM
3045
N
VAL
A
415
5.474
−27.567
4.316
1.00
46.53
N


ATOM
3046
CA
VAL
A
415
4.210
−28.270
4.277
1.00
47.31
C


ATOM
3048
CB
VAL
A
415
3.962
−28.994
2.935
1.00
47.46
C


ATOM
3050
CG1
VAL
A
415
2.753
−29.878
3.047
1.00
46.40
C


ATOM
3054
CG2
VAL
A
415
3.787
−27.983
1.792
1.00
46.46
C


ATOM
3058
C
VAL
A
415
4.109
−29.280
5.410
1.00
48.55
C


ATOM
3059
O
VAL
A
415
3.050
−29.391
6.040
1.00
49.95
O


ATOM
3061
N
ILE
A
416
5.186
−30.010
5.688
1.00
48.88
N


ATOM
3062
CA
ILE
A
416
5.173
−30.997
6.780
1.00
48.60
C


ATOM
3064
CB
ILE
A
416
6.528
−31.767
6.841
1.00
48.40
C


ATOM
3066
CG1
ILE
A
416
6.613
−32.784
5.692
1.00
47.72
C


ATOM
3069
CD1
ILE
A
416
7.991
−33.448
5.558
1.00
44.52
C


ATOM
3073
CG2
ILE
A
416
6.706
−32.491
8.185
1.00
47.39
C


ATOM
3077
C
ILE
A
416
4.891
−30.344
8.145
1.00
48.97
C


ATOM
3078
O
ILE
A
416
4.133
−30.874
8.964
1.00
48.10
O


ATOM
3080
N
LEU
A
417
5.544
−29.214
8.403
1.00
49.89
N


ATOM
3081
CA
LEU
A
417
5.387
−28.525
9.681
1.00
51.00
C


ATOM
3083
CB
LEU
A
417
6.364
−27.379
9.786
1.00
50.44
C


ATOM
3086
CG
LEU
A
417
6.325
−26.591
11.083
1.00
50.45
C


ATOM
3088
CD1
LEU
A
417
6.566
−27.505
12.273
1.00
48.96
C


ATOM
3092
CD2
LEU
A
417
7.357
−25.489
11.024
1.00
50.19
C


ATOM
3096
C
LEU
A
417
3.943
−28.013
9.837
1.00
52.24
C


ATOM
3097
O
LEU
A
417
3.329
−28.186
10.873
1.00
52.75
O


ATOM
3099
N
PHE
A
418
3.410
−27.416
8.786
1.00
53.54
N


ATOM
3100
CA
PHE
A
418
2.005
−27.014
8.742
1.00
55.13
C


ATOM
3102
CB
PHE
A
418
1.663
−26.578
7.314
1.00
55.27
C


ATOM
3105
CG
PHE
A
418
0.307
−25.957
7.155
1.00
56.07
C


ATOM
3106
CD1
PHE
A
418
−0.837
−26.756
7.074
1.00
57.49
C


ATOM
3108
CE1
PHE
A
418
−2.102
−26.188
6.886
1.00
56.24
C


ATOM
3110
CZ
PHE
A
418
−2.223
−24.821
6.754
1.00
56.24
C


ATOM
3112
CE2
PHE
A
418
−1.081
−24.006
6.812
1.00
56.64
C


ATOM
3114
CD2
PHE
A
418
0.177
−24.580
6.996
1.00
55.63
C


ATOM
3116
C
PHE
A
418
1.109
−28.168
9.193
1.00
55.76
C


ATOM
3117
O
PHE
A
418
0.436
−28.061
10.217
1.00
56.47
O


ATOM
3119
N
ILE
A
419
1.146
−29.272
8.451
1.00
56.11
N


ATOM
3120
CA
ILE
A
419
0.380
−30.475
8.766
1.00
56.41
C


ATOM
3122
CB
ILE
A
419
0.805
−31.653
7.864
1.00
56.61
C


ATOM
3124
CG1
ILE
A
419
0.214
−31.469
6.466
1.00
56.42
C


ATOM
3127
CD1
ILE
A
419
0.753
−32.440
5.436
1.00
56.52
C


ATOM
3131
CG2
ILE
A
419
0.364
−33.001
8.438
1.00
56.53
C


ATOM
3135
C
ILE
A
419
0.529
−30.882
10.213
1.00
57.00
C


ATOM
3136
O
ILE
A
419
−0.463
−31.038
10.915
1.00
57.28
O


ATOM
3138
N
CYS
A
420
1.766
−31.029
10.664
1.00
57.65
N


ATOM
3139
CA
CYS
A
420
2.043
−31.457
12.035
1.00
58.05
C


ATOM
3141
CB
CYS
A
420
3.548
−31.476
12.283
1.00
58.22
C


ATOM
3144
SG
CYS
A
420
4.347
−32.928
11.633
1.00
59.26
S


ATOM
3146
C
CYS
A
420
1.439
−30.549
13.079
1.00
58.71
C


ATOM
3147
O
CYS
A
420
0.931
−31.022
14.093
1.00
59.38
O


ATOM
3149
N
LEU
A
421
1.546
−29.241
12.844
1.00
59.35
N


ATOM
3150
CA
LEU
A
421
1.089
−28.218
13.797
1.00
59.60
C


ATOM
3152
CB
LEU
A
421
1.644
−26.830
13.415
1.00
59.24
C


ATOM
3155
CG
LEU
A
421
3.104
−26.487
13.760
1.00
58.85
C


ATOM
3157
CD1
LEU
A
421
3.498
−25.088
13.239
1.00
56.81
C


ATOM
3161
CD2
LEU
A
421
3.371
−26.580
15.265
1.00
58.40
C


ATOM
3165
C
LEU
A
421
−0.448
−28.153
13.895
1.00
59.82
C


ATOM
3166
O
LEU
A
421
−0.982
−27.886
14.955
1.00
59.45
O


ATOM
3168
N
SER
A
422
−1.126
−28.440
12.786
1.00
60.46
N


ATOM
3169
CA
SER
A
422
−2.543
−28.127
12.598
1.00
60.58
C


ATOM
3171
CB
SER
A
422
−2.681
−27.278
11.348
1.00
60.19
C


ATOM
3174
OG
SER
A
422
−2.666
−28.127
10.204
1.00
59.49
O


ATOM
3176
C
SER
A
422
−3.448
−29.329
12.386
1.00
61.17
C


ATOM
3177
O
SER
A
422
−4.646
−29.172
12.390
1.00
61.93
O


ATOM
3179
N
GLY
A
423
−2.895
−30.508
12.114
1.00
61.91
N


ATOM
3180
CA
GLY
A
423
−3.700
−31.701
11.843
1.00
61.68
C


ATOM
3183
C
GLY
A
423
−4.249
−31.775
10.438
1.00
62.09
C


ATOM
3184
O
GLY
A
423
−4.795
−32.810
10.053
1.00
61.95
O


ATOM
3186
N
TYR
A
424
−4.094
−30.697
9.660
1.00
62.86
N


ATOM
3187
CA
TYR
A
424
−4.637
−30.632
8.287
1.00
63.28
C


ATOM
3189
CB
TYR
A
424
−5.977
−29.831
8.274
1.00
63.23
C


ATOM
3192
CG
TYR
A
424
−5.845
−28.316
8.271
1.00
61.08
C


ATOM
3193
CD1
TYR
A
424
−5.732
−27.606
9.457
1.00
59.53
C


ATOM
3195
CE1
TYR
A
424
−5.600
−26.228
9.467
1.00
58.10
C


ATOM
3197
CZ
TYR
A
424
−5.593
−25.533
8.287
1.00
58.52
C


ATOM
3198
OH
TYR
A
424
−5.444
−24.152
8.325
1.00
60.25
O


ATOM
3200
CE2
TYR
A
424
−5.712
−26.206
7.085
1.00
58.95
C


ATOM
3202
CD2
TYR
A
424
−5.840
−27.599
7.083
1.00
60.35
C


ATOM
3204
C
TYR
A
424
−3.633
−30.054
7.245
1.00
64.16
C


ATOM
3205
O
TYR
A
424
−2.758
−29.253
7.595
1.00
63.66
O


ATOM
3207
N
PRO
A
425
−3.782
−30.452
5.957
1.00
65.03
N


ATOM
3208
CA
PRO
A
425
−2.926
−29.988
4.864
1.00
65.60
C


ATOM
3210
CB
PRO
A
425
−3.262
−30.949
3.722
1.00
65.60
C


ATOM
3213
CG
PRO
A
425
−4.667
−31.323
3.968
1.00
65.51
C


ATOM
3216
CD
PRO
A
425
−4.773
−31.429
5.472
1.00
64.99
C


ATOM
3219
C
PRO
A
425
−3.238
−28.583
4.411
1.00
66.19
C


ATOM
3220
O
PRO
A
425
−4.401
−28.225
4.333
1.00
66.80
O


ATOM
3221
N
PRO
A
426
−2.207
−27.798
4.077
1.00
66.99
N


ATOM
3222
CA
PRO
A
426
−2.374
−26.426
3.641
1.00
67.39
C


ATOM
3224
CB
PRO
A
426
−0.944
−25.895
3.670
1.00
67.75
C


ATOM
3227
CG
PRO
A
426
−0.114
−27.065
3.418
1.00
66.98
C


ATOM
3230
CD
PRO
A
426
−0.791
−28.200
4.075
1.00
66.70
C


ATOM
3233
C
PRO
A
426
−2.916
−26.280
2.235
1.00
68.08
C


ATOM
3234
O
PRO
A
426
−3.491
−25.250
1.914
1.00
68.23
O


ATOM
3235
N
PHE
A
427
−2.677
−27.269
1.389
1.00
69.04
N


ATOM
3236
CA
PHE
A
427
−3.204
−27.267
0.047
1.00
70.14
C


ATOM
3238
CB
PHE
A
427
−2.079
−27.113
−0.961
1.00
70.17
C


ATOM
3241
CG
PHE
A
427
−1.124
−26.030
−0.621
1.00
69.52
C


ATOM
3242
CD1
PHE
A
427
−1.453
−24.711
−0.850
1.00
68.89
C


ATOM
3244
CE1
PHE
A
427
−0.573
−23.703
−0.520
1.00
68.15
C


ATOM
3246
CZ
PHE
A
427
0.645
−24.014
0.038
1.00
67.52
C


ATOM
3248
CE2
PHE
A
427
0.981
−25.327
0.266
1.00
67.49
C


ATOM
3250
CD2
PHE
A
427
0.104
−26.323
−0.054
1.00
68.46
C


ATOM
3252
C
PHE
A
427
−3.908
−28.572
−0.206
1.00
71.56
C


ATOM
3253
O
PHE
A
427
−3.306
−29.619
−0.108
1.00
71.96
O


ATOM
3255
N
SER
A
428
−5.193
−28.502
−0.507
1.00
73.56
N


ATOM
3256
CA
SER
A
428
−5.948
−29.653
−0.987
1.00
74.95
C


ATOM
3258
CB
SER
A
428
−6.370
−30.569
0.160
1.00
75.15
C


ATOM
3261
OG
SER
A
428
−7.155
−29.876
1.101
1.00
75.42
O


ATOM
3263
C
SER
A
428
−7.175
−29.177
−1.735
1.00
76.27
C


ATOM
3264
O
SER
A
428
−7.504
−27.990
−1.735
1.00
76.12
O


ATOM
3266
N
GLU
A
429
−7.852
−30.115
−2.379
1.00
78.09
N


ATOM
3267
CA
GLU
A
429
−9.076
−29.802
−3.100
1.00
79.46
C


ATOM
3269
CB
GLU
A
429
−9.111
−30.626
−4.389
1.00
79.70
C


ATOM
3272
CG
GLU
A
429
−7.876
−30.324
−5.274
1.00
80.16
C


ATOM
3275
CD
GLU
A
429
−7.780
−31.149
−6.549
1.00
80.27
C


ATOM
3276
OE1
GLU
A
429
−8.103
−32.353
−6.507
1.00
80.90
O


ATOM
3277
OE2
GLU
A
429
−7.347
−30.592
−7.588
1.00
79.70
O


ATOM
3278
C
GLU
A
429
−10.334
−29.964
−2.206
1.00
80.53
C


ATOM
3279
O
GLU
A
429
−11.454
−29.717
−2.662
1.00
80.66
O


ATOM
3281
N
HIS
A
430
−10.123
−30.318
−0.928
1.00
81.63
N


ATOM
3282
CA
HIS
A
430
−11.188
−30.438
0.081
1.00
82.67
C


ATOM
3284
CB
HIS
A
430
−10.666
−31.180
1.328
1.00
83.11
C


ATOM
3287
CG
HIS
A
430
−11.684
−31.350
2.429
1.00
85.22
C


ATOM
3288
ND1
HIS
A
430
−12.459
−32.487
2.566
1.00
86.32
N


ATOM
3290
CE1
HIS
A
430
−13.239
−32.366
3.627
1.00
86.71
C


ATOM
3292
NE2
HIS
A
430
−12.994
−31.197
4.193
1.00
87.13
N


ATOM
3294
CD2
HIS
A
430
−12.025
−30.542
3.465
1.00
86.69
C


ATOM
3296
C
HIS
A
430
−11.717
−29.071
0.501
1.00
83.07
C


ATOM
3297
O
HIS
A
430
−11.036
−28.334
1.226
1.00
83.17
O


ATOM
3299
N
ARG
A
431
−12.942
−28.762
0.064
1.00
83.42
N


ATOM
3300
CA
ARG
A
431
−13.622
−27.492
0.362
1.00
83.44
C


ATOM
3302
CB
ARG
A
431
−13.842
−27.296
1.883
1.00
83.82
C


ATOM
3305
CG
ARG
A
431
−14.688
−28.415
2.562
1.00
85.30
C


ATOM
3308
CD
ARG
A
431
−15.776
−27.870
3.536
1.00
87.34
C


ATOM
3311
NE
ARG
A
431
−15.574
−28.175
4.964
1.00
88.75
N


ATOM
3313
CZ
ARG
A
431
−16.243
−27.595
5.977
1.00
90.15
C


ATOM
3314
NH1
ARG
A
431
−17.159
−26.648
5.763
1.00
90.54
N


ATOM
3317
NH2
ARG
A
431
−15.985
−27.948
7.232
1.00
90.64
N


ATOM
3320
C
ARG
A
431
−12.907
−26.279
−0.273
1.00
82.97
C


ATOM
3321
O
ARG
A
431
−12.322
−25.442
0.432
1.00
83.31
O


ATOM
3323
N
THR
A
432
−12.941
−26.233
−1.608
1.00
81.92
N


ATOM
3324
CA
THR
A
432
−12.619
−25.040
−2.415
1.00
81.04
C


ATOM
3326
CB
THR
A
432
−11.147
−24.557
−2.306
1.00
81.16
C


ATOM
3328
OG1
THR
A
432
−10.294
−25.668
−1.999
1.00
82.51
O


ATOM
3330
CG2
THR
A
432
−10.988
−23.452
−1.254
1.00
81.57
C


ATOM
3334
C
THR
A
432
−12.845
−25.383
−3.872
1.00
79.95
C


ATOM
3335
O
THR
A
432
−12.871
−26.561
−4.251
1.00
79.64
O


ATOM
3337
N
GLN
A
433
−12.998
−24.349
−4.687
1.00
78.65
N


ATOM
3338
CA
GLN
A
433
−13.035
−24.520
−6.136
1.00
77.89
C


ATOM
3340
CB
GLN
A
433
−14.074
−23.578
−6.777
1.00
78.29
C


ATOM
3343
CG
GLN
A
433
−15.518
−24.142
−6.813
1.00
79.96
C


ATOM
3346
CD
GLN
A
433
−16.387
−23.723
−5.606
1.00
82.44
C


ATOM
3347
OE1
GLN
A
433
−15.885
−23.476
−4.499
1.00
83.03
O


ATOM
3348
NE2
GLN
A
433
−17.706
−23.654
−5.828
1.00
83.17
N


ATOM
3351
C
GLN
A
433
−11.648
−24.308
−6.753
1.00
76.18
C


ATOM
3352
O
GLN
A
433
−11.374
−24.808
−7.846
1.00
75.99
O


ATOM
3354
N
VAL
A
434
−10.778
−23.577
−6.050
1.00
74.33
N


ATOM
3355
CA
VAL
A
434
−9.424
−23.272
−6.551
1.00
72.65
C


ATOM
3357
CB
VAL
A
434
−8.634
−22.318
−5.558
1.00
72.89
C


ATOM
3359
CG1
VAL
A
434
−8.462
−22.950
−4.162
1.00
73.31
C


ATOM
3363
CG2
VAL
A
434
−7.286
−21.873
−6.152
1.00
72.29
C


ATOM
3367
C
VAL
A
434
−8.663
−24.568
−6.853
1.00
70.67
C


ATOM
3368
O
VAL
A
434
−8.648
−25.484
−6.033
1.00
70.10
O


ATOM
3370
N
SER
A
435
−8.085
−24.652
−8.052
1.00
68.66
N


ATOM
3371
CA
SER
A
435
−7.326
−25.831
−8.472
1.00
67.06
C


ATOM
3373
CB
SER
A
435
−7.005
−25.784
−9.964
1.00
66.93
C


ATOM
3376
OG
SER
A
435
−5.824
−25.038
−10.233
1.00
67.15
O


ATOM
3378
C
SER
A
435
−6.026
−25.906
−7.690
1.00
66.12
C


ATOM
3379
O
SER
A
435
−5.320
−24.904
−7.590
1.00
65.87
O


ATOM
3381
N
LEU
A
436
−5.718
−27.098
−7.161
1.00
64.78
N


ATOM
3382
CA
LEU
A
436
−4.554
−27.347
−6.297
1.00
63.53
C


ATOM
3384
CB
LEU
A
436
−4.376
−28.856
−6.094
1.00
63.63
C


ATOM
3387
CG
LEU
A
436
−3.477
−29.414
−4.981
1.00
64.34
C


ATOM
3389
CD1
LEU
A
436
−3.678
−28.754
−3.606
1.00
64.94
C


ATOM
3393
CD2
LEU
A
436
−3.712
−30.913
−4.877
1.00
64.95
C


ATOM
3397
C
LEU
A
436
−3.275
−26.705
−6.852
1.00
62.11
C


ATOM
3398
O
LEU
A
436
−2.483
−26.139
−6.101
1.00
61.06
O


ATOM
3400
N
LYS
A
437
−3.118
−26.750
−8.168
1.00
60.71
N


ATOM
3401
CA
LYS
A
437
−2.026
−26.064
−8.826
1.00
60.41
C


ATOM
3403
CB
LYS
A
437
−2.090
−26.241
−10.343
1.00
59.74
C


ATOM
3406
CG
LYS
A
437
−0.895
−25.644
−11.064
1.00
60.54
C


ATOM
3409
CD
LYS
A
437
−1.021
−25.562
−12.598
1.00
61.17
C


ATOM
3412
CE
LYS
A
437
0.338
−25.202
−13.220
1.00
61.82
C


ATOM
3415
NZ
LYS
A
437
0.338
−24.799
−14.663
1.00
62.92
N


ATOM
3419
C
LYS
A
437
−2.051
−24.575
−8.495
1.00
60.64
C


ATOM
3420
O
LYS
A
437
−1.033
−23.979
−8.168
1.00
60.95
O


ATOM
3422
N
ASP
A
438
−3.218
−23.960
−8.595
1.00
60.83
N


ATOM
3423
CA
ASP
A
438
−3.312
−22.522
−8.380
1.00
60.32
C


ATOM
3425
CB
ASP
A
438
−4.652
−22.001
−8.905
1.00
60.32
C


ATOM
3428
CG
ASP
A
438
−4.688
−21.930
−10.426
1.00
60.99
C


ATOM
3429
OD1
ASP
A
438
−3.657
−22.180
−11.088
1.00
59.16
O


ATOM
3430
OD2
ASP
A
438
−5.764
−21.609
−10.971
1.00
65.12
O


ATOM
3431
C
ASP
A
438
−3.053
−22.140
−6.920
1.00
59.49
C


ATOM
3432
O
ASP
A
438
−2.441
−21.100
−6.649
1.00
59.64
O


ATOM
3434
N
GLN
A
439
−3.464
−22.995
−5.988
1.00
58.54
N


ATOM
3435
CA
GLN
A
439
−3.223
−22.726
−4.570
1.00
57.88
C


ATOM
3437
CB
GLN
A
439
−3.863
−23.784
−3.651
1.00
57.98
C


ATOM
3440
CG
GLN
A
439
−5.308
−24.182
−3.988
1.00
58.93
C


ATOM
3443
CD
GLN
A
439
−5.909
−25.163
−2.973
1.00
59.83
C


ATOM
3444
OE1
GLN
A
439
−5.430
−25.300
−1.836
1.00
58.68
O


ATOM
3445
NE2
GLN
A
439
−6.959
−25.852
−3.390
1.00
58.65
N


ATOM
3448
C
GLN
A
439
−1.713
−22.689
−4.322
1.00
56.94
C


ATOM
3449
O
GLN
A
439
−1.203
−21.760
−3.695
1.00
57.60
O


ATOM
3451
N
ILE
A
440
−1.001
−23.691
−4.832
1.00
55.00
N


ATOM
3452
CA
ILE
A
440
0.406
−23.830
−4.534
1.00
53.55
C


ATOM
3454
CB
ILE
A
440
0.953
−25.232
−4.953
1.00
53.04
C


ATOM
3456
CG1
ILE
A
440
0.335
−26.320
−4.091
1.00
49.96
C


ATOM
3459
CD1
ILE
A
440
0.445
−27.651
−4.729
1.00
47.57
C


ATOM
3463
CG2
ILE
A
440
2.455
−25.316
−4.810
1.00
51.53
C


ATOM
3467
C
ILE
A
440
1.177
−22.689
−5.184
1.00
53.77
C


ATOM
3468
O
ILE
A
440
1.921
−21.986
−4.507
1.00
52.55
O


ATOM
3470
N
THR
A
441
0.983
−22.467
−6.477
1.00
54.53
N


ATOM
3471
CA
THR
A
441
1.766
−21.427
−7.160
1.00
56.00
C


ATOM
3473
CB
THR
A
441
1.595
−21.456
−8.674
1.00
55.87
C


ATOM
3475
OG1
THR
A
441
0.207
−21.393
−8.980
1.00
57.84
O


ATOM
3477
CG2
THR
A
441
2.193
−22.707
−9.250
1.00
54.58
C


ATOM
3481
C
THR
A
441
1.488
−20.000
−6.674
1.00
57.06
C


ATOM
3482
O
THR
A
441
2.366
−19.148
−6.741
1.00
56.89
O


ATOM
3484
N
SER
A
442
0.279
−19.742
−6.191
1.00
58.94
N


ATOM
3485
CA
SER
A
442
−0.025
−18.450
−5.582
1.00
60.26
C


ATOM
3487
CB
SER
A
442
−1.532
−18.189
−5.586
1.00
60.01
C


ATOM
3490
OG
SER
A
442
−2.166
−18.782
−4.459
1.00
60.26
O


ATOM
3492
C
SER
A
442
0.531
−18.410
−4.149
1.00
61.69
C


ATOM
3493
O
SER
A
442
0.999
−17.369
−3.688
1.00
62.08
O


ATOM
3495
N
GLY
A
443
0.481
−19.548
−3.457
1.00
63.15
N


ATOM
3496
CA
GLY
A
443
0.868
−19.633
−2.036
1.00
64.24
C


ATOM
3499
C
GLY
A
443
−0.272
−19.393
−1.054
1.00
65.51
C


ATOM
3500
O
GLY
A
443
−0.066
−19.339
0.157
1.00
65.49
O


ATOM
3502
N
LYS
A
444
−1.488
−19.251
−1.566
1.00
67.13
N


ATOM
3503
CA
LYS
A
444
−2.641
−19.005
−0.720
1.00
68.14
C


ATOM
3505
CB
LYS
A
444
−3.788
−18.418
−1.549
1.00
68.59
C


ATOM
3508
CG
LYS
A
444
−3.504
−16.997
−2.093
1.00
69.14
C


ATOM
3511
CD
LYS
A
444
−4.504
−16.596
−3.198
1.00
70.30
C


ATOM
3514
CE
LYS
A
444
−4.738
−15.076
−3.282
1.00
71.05
C


ATOM
3517
NZ
LYS
A
444
−3.530
−14.308
−3.715
1.00
70.57
N


ATOM
3521
C
LYS
A
444
−3.037
−20.318
−0.056
1.00
68.76
C


ATOM
3522
O
LYS
A
444
−3.804
−21.101
−0.603
1.00
68.82
O


ATOM
3524
N
TYR
A
445
−2.477
−20.552
1.123
1.00
69.26
N


ATOM
3525
CA
TYR
A
445
−2.726
−21.779
1.869
1.00
69.63
C


ATOM
3527
CB
TYR
A
445
−1.554
−22.087
2.817
1.00
69.79
C


ATOM
3530
CG
TYR
A
445
−1.065
−20.887
3.605
1.00
69.19
C


ATOM
3531
CD1
TYR
A
445
−1.762
−20.416
4.720
1.00
69.61
C


ATOM
3533
CE1
TYR
A
445
−1.324
−19.314
5.435
1.00
69.55
C


ATOM
3535
CZ
TYR
A
445
−0.170
−18.658
5.041
1.00
70.95
C


ATOM
3536
OH
TYR
A
445
0.296
−17.552
5.735
1.00
71.08
O


ATOM
3538
CE2
TYR
A
445
0.538
−19.113
3.937
1.00
70.28
C


ATOM
3540
CD2
TYR
A
445
0.084
−20.223
3.229
1.00
68.92
C


ATOM
3542
C
TYR
A
445
−3.996
−21.665
2.685
1.00
70.10
C


ATOM
3543
O
TYR
A
445
−4.337
−20.595
3.160
1.00
69.71
O


ATOM
3545
N
ASN
A
446
−4.660
−22.797
2.886
1.00
71.08
N


ATOM
3546
CA
ASN
A
446
−5.865
−22.861
3.696
1.00
71.63
C


ATOM
3548
CB
ASN
A
446
−6.524
−24.224
3.511
1.00
71.71
C


ATOM
3551
CG
ASN
A
446
−7.997
−24.214
3.854
1.00
72.24
C


ATOM
3552
OD1
ASN
A
446
−8.830
−24.058
2.968
1.00
73.35
O


ATOM
3553
ND2
ASN
A
446
−8.328
−24.379
5.136
1.00
71.49
N


ATOM
3556
C
ASN
A
446
−5.582
−22.580
5.184
1.00
72.35
C


ATOM
3557
O
ASN
A
446
−5.228
−23.477
5.940
1.00
71.86
O


ATOM
3559
N
PHE
A
447
−5.729
−21.318
5.582
1.00
73.47
N


ATOM
3560
CA
PHE
A
447
−5.599
−20.900
6.984
1.00
74.56
C


ATOM
3562
CB
PHE
A
447
−5.083
−19.474
7.036
1.00
74.58
C


ATOM
3565
CG
PHE
A
447
−4.834
−18.985
8.417
1.00
75.74
C


ATOM
3566
CD1
PHE
A
447
−3.925
−19.637
9.238
1.00
77.05
C


ATOM
3568
CE1
PHE
A
447
−3.681
−19.188
10.534
1.00
77.94
C


ATOM
3570
CZ
PHE
A
447
−4.346
−18.073
11.007
1.00
77.80
C


ATOM
3572
CE2
PHE
A
447
−5.252
−17.408
10.181
1.00
77.25
C


ATOM
3574
CD2
PHE
A
447
−5.490
−17.865
8.900
1.00
76.65
C


ATOM
3576
C
PHE
A
447
−6.927
−20.973
7.747
1.00
75.24
C


ATOM
3577
O
PHE
A
447
−7.941
−20.519
7.248
1.00
75.85
O


ATOM
3579
N
ILE
A
448
−6.913
−21.533
8.954
1.00
76.05
N


ATOM
3580
CA
ILE
A
448
−8.130
−21.739
9.749
1.00
76.78
C


ATOM
3582
CB
ILE
A
448
−8.575
−23.211
9.744
1.00
76.67
C


ATOM
3584
CG1
ILE
A
448
−8.990
−23.646
8.335
1.00
76.17
C


ATOM
3587
CD1
ILE
A
448
−9.447
−25.085
8.258
1.00
75.25
C


ATOM
3591
CG2
ILE
A
448
−9.722
−23.414
10.722
1.00
76.47
C


ATOM
3595
C
ILE
A
448
−7.885
−21.316
11.197
1.00
77.87
C


ATOM
3596
O
ILE
A
448
−7.384
−22.107
12.002
1.00
78.10
O


ATOM
3598
N
PRO
A
449
−8.253
−20.070
11.545
1.00
79.21
N


ATOM
3599
CA
PRO
A
449
−7.814
−19.520
12.842
1.00
79.97
C


ATOM
3601
CB
PRO
A
449
−8.489
−18.135
12.888
1.00
80.05
C


ATOM
3604
CG
PRO
A
449
−8.720
−17.772
11.437
1.00
79.51
C


ATOM
3607
CD
PRO
A
449
−9.000
−19.075
10.741
1.00
79.13
C


ATOM
3610
C
PRO
A
449
−8.145
−20.342
14.106
1.00
80.64
C


ATOM
3611
O
PRO
A
449
−7.317
−20.393
15.022
1.00
81.26
O


ATOM
3612
N
GLU
A
450
−9.313
−20.980
14.169
1.00
81.17
N


ATOM
3613
CA
GLU
A
450
−9.707
−21.711
15.393
1.00
81.71
C


ATOM
3615
CB
GLU
A
450
−11.217
−22.033
15.464
1.00
81.99
C


ATOM
3618
CG
GLU
A
450
−11.841
−22.668
14.208
1.00
83.45
C


ATOM
3621
CD
GLU
A
450
−12.314
−21.631
13.173
1.00
84.96
C


ATOM
3622
OE1
GLU
A
450
−11.941
−20.439
13.295
1.00
84.92
O


ATOM
3623
OE2
GLU
A
450
−13.048
−22.013
12.228
1.00
85.98
O


ATOM
3624
C
GLU
A
450
−8.905
−22.978
15.586
1.00
81.74
C


ATOM
3625
O
GLU
A
450
−8.828
−23.498
16.702
1.00
82.06
O


ATOM
3627
N
VAL
A
451
−8.325
−23.497
14.508
1.00
81.59
N


ATOM
3628
CA
VAL
A
451
−7.385
−24.596
14.647
1.00
81.43
C


ATOM
3630
CB
VAL
A
451
−7.376
−25.496
13.405
1.00
81.67
C


ATOM
3632
CG1
VAL
A
451
−6.375
−26.634
13.574
1.00
81.63
C


ATOM
3636
CG2
VAL
A
451
−8.769
−26.066
13.164
1.00
81.69
C


ATOM
3640
C
VAL
A
451
−5.989
−24.049
14.995
1.00
81.02
C


ATOM
3641
O
VAL
A
451
−5.286
−24.653
15.802
1.00
81.00
O


ATOM
3643
N
TRP
A
452
−5.621
−22.891
14.438
1.00
80.50
N


ATOM
3644
CA
TRP
A
452
−4.299
−22.274
14.685
1.00
80.35
C


ATOM
3646
CB
TRP
A
452
−3.892
−21.373
13.512
1.00
80.27
C


ATOM
3649
CG
TRP
A
452
−3.405
−22.175
12.367
1.00
80.45
C


ATOM
3650
CD1
TRP
A
452
−4.129
−22.597
11.299
1.00
80.94
C


ATOM
3652
NE1
TRP
A
452
−3.347
−23.351
10.459
1.00
80.66
N


ATOM
3654
CE2
TRP
A
452
−2.087
−23.435
10.987
1.00
80.06
C


ATOM
3655
CD2
TRP
A
452
−2.089
−22.708
12.194
1.00
79.74
C


ATOM
3656
CE3
TRP
A
452
−0.910
−22.636
12.938
1.00
79.12
C


ATOM
3658
CZ3
TRP
A
452
0.217
−23.283
12.459
1.00
78.79
C


ATOM
3660
CH2
TRP
A
452
0.190
−23.987
11.249
1.00
78.09
C


ATOM
3662
CZ2
TRP
A
452
−0.948
−24.078
10.502
1.00
79.05
C


ATOM
3664
C
TRP
A
452
−4.151
−21.475
15.977
1.00
80.44
C


ATOM
3665
O
TRP
A
452
−3.026
−21.289
16.462
1.00
80.41
O


ATOM
3667
N
ALA
A
453
−5.267
−20.971
16.509
1.00
80.32
N


ATOM
3668
CA
ALA
A
453
−5.274
−20.236
17.780
1.00
79.90
C


ATOM
3670
CB
ALA
A
453
−6.709
−19.984
18.232
1.00
79.89
C


ATOM
3674
C
ALA
A
453
−4.503
−21.003
18.854
1.00
79.42
C


ATOM
3675
O
ALA
A
453
−3.779
−20.404
19.648
1.00
79.41
O


ATOM
3677
N
GLU
A
454
−4.670
−22.327
18.862
1.00
78.97
N


ATOM
3678
CA
GLU
A
454
−3.826
−23.242
19.660
1.00
78.65
C


ATOM
3680
CB
GLU
A
454
−4.025
−24.708
19.221
1.00
78.87
C


ATOM
3683
CG
GLU
A
454
−5.171
−25.444
19.910
1.00
79.73
C


ATOM
3686
CD
GLU
A
454
−6.516
−25.170
19.271
1.00
81.49
C


ATOM
3687
OE1
GLU
A
454
−7.426
−26.019
19.416
1.00
82.42
O


ATOM
3688
OE2
GLU
A
454
−6.667
−24.112
18.619
1.00
82.36
O


ATOM
3689
C
GLU
A
454
−2.333
−22.929
19.553
1.00
77.59
C


ATOM
3690
O
GLU
A
454
−1.626
−22.920
20.553
1.00
77.58
O


ATOM
3692
N
VAL
A
455
−1.863
−22.672
18.335
1.00
76.41
N


ATOM
3693
CA
VAL
A
455
−0.423
−22.612
18.040
1.00
75.31
C


ATOM
3695
CB
VAL
A
455
−0.174
−23.112
16.597
1.00
75.16
C


ATOM
3697
CG1
VAL
A
455
1.314
−23.147
16.269
1.00
75.38
C


ATOM
3701
CG2
VAL
A
455
−0.794
−24.482
16.420
1.00
74.75
C


ATOM
3705
C
VAL
A
455
0.198
−21.212
18.249
1.00
74.21
C


ATOM
3706
O
VAL
A
455
−0.455
−20.192
18.043
1.00
74.16
O


ATOM
3708
N
SER
A
456
1.465
−21.183
18.652
1.00
73.01
N


ATOM
3709
CA
SER
A
456
2.176
−19.934
18.894
1.00
72.31
C


ATOM
3711
CB
SER
A
456
3.545
−20.205
19.536
1.00
72.27
C


ATOM
3714
OG
SER
A
456
4.556
−20.429
18.560
1.00
71.70
O


ATOM
3716
C
SER
A
456
2.369
−19.147
17.606
1.00
71.90
C


ATOM
3717
O
SER
A
456
2.256
−19.698
16.511
1.00
71.81
O


ATOM
3719
N
GLU
A
457
2.669
−17.858
17.747
1.00
71.42
N


ATOM
3720
CA
GLU
A
457
2.956
−16.988
16.599
1.00
70.91
C


ATOM
3722
CB
GLU
A
457
3.038
−15.513
17.020
1.00
71.26
C


ATOM
3725
CG
GLU
A
457
1.777
−14.908
17.609
1.00
74.10
C


ATOM
3728
CD
GLU
A
457
2.090
−13.757
18.585
1.00
77.16
C


ATOM
3729
OE1
GLU
A
457
1.618
−12.617
18.343
1.00
78.32
O


ATOM
3730
OE2
GLU
A
457
2.821
−13.999
19.588
1.00
77.62
O


ATOM
3731
C
GLU
A
457
4.288
−17.335
15.938
1.00
69.45
C


ATOM
3732
O
GLU
A
457
4.406
−17.242
14.714
1.00
69.10
O


ATOM
3734
N
LYS
A
458
5.294
−17.674
16.755
1.00
67.93
N


ATOM
3735
CA
LYS
A
458
6.642
−18.011
16.259
1.00
66.84
C


ATOM
3737
CB
LYS
A
458
7.599
−18.290
17.419
1.00
66.96
C


ATOM
3740
CG
LYS
A
458
7.885
−17.108
18.324
1.00
67.37
C


ATOM
3743
CD
LYS
A
458
8.794
−17.539
19.457
1.00
68.52
C


ATOM
3746
CE
LYS
A
458
9.059
−16.439
20.488
1.00
69.47
C


ATOM
3749
NZ
LYS
A
458
10.282
−15.633
20.194
1.00
70.38
N


ATOM
3753
C
LYS
A
458
6.591
−19.237
15.333
1.00
65.32
C


ATOM
3754
O
LYS
A
458
7.110
−19.199
14.223
1.00
64.20
O


ATOM
3756
N
ALA
A
459
5.926
−20.299
15.797
1.00
64.03
N


ATOM
3757
CA
ALA
A
459
5.685
−21.519
14.999
1.00
62.98
C


ATOM
3759
CB
ALA
A
459
4.845
−22.497
15.773
1.00
62.81
C


ATOM
3763
C
ALA
A
459
5.026
−21.233
13.655
1.00
62.13
C


ATOM
3764
O
ALA
A
459
5.403
−21.814
12.624
1.00
62.18
O


ATOM
3766
N
LEU
A
460
4.047
−20.339
13.661
1.00
61.02
N


ATOM
3767
CA
LEU
A
460
3.373
−19.933
12.424
1.00
60.18
C


ATOM
3769
CB
LEU
A
460
2.045
−19.223
12.720
1.00
60.37
C


ATOM
3772
CG
LEU
A
460
1.178
−18.721
11.545
1.00
61.36
C


ATOM
3774
CD1
LEU
A
460
0.794
−19.856
10.561
1.00
60.72
C


ATOM
3778
CD2
LEU
A
460
−0.074
−18.033
12.093
1.00
60.57
C


ATOM
3782
C
LEU
A
460
4.260
−19.038
11.584
1.00
58.95
C


ATOM
3783
O
LEU
A
460
4.186
−19.077
10.366
1.00
59.20
O


ATOM
3785
N
ASP
A
461
5.092
−18.228
12.223
1.00
58.21
N


ATOM
3786
CA
ASP
A
461
6.012
−17.342
11.494
1.00
57.65
C


ATOM
3788
CB
ASP
A
461
6.742
−16.389
12.445
1.00
57.66
C


ATOM
3791
CG
ASP
A
461
7.592
−15.380
11.708
1.00
59.03
C


ATOM
3792
OD1
ASP
A
461
7.003
−14.480
11.072
1.00
59.94
O


ATOM
3793
OD2
ASP
A
461
8.845
−15.493
11.755
1.00
60.28
O


ATOM
3794
C
ASP
A
461
7.032
−18.143
10.682
1.00
56.90
C


ATOM
3795
O
ASP
A
461
7.352
−17.775
9.560
1.00
57.73
O


ATOM
3797
N
LEU
A
462
7.542
−19.233
11.247
1.00
55.92
N


ATOM
3798
CA
LEU
A
462
8.441
−20.128
10.516
1.00
55.25
C


ATOM
3800
CB
LEU
A
462
8.945
−21.229
11.433
1.00
55.27
C


ATOM
3803
CG
LEU
A
462
10.099
−22.077
10.903
1.00
55.00
C


ATOM
3805
CD1
LEU
A
462
11.276
−21.221
10.458
1.00
51.17
C


ATOM
3809
CD2
LEU
A
462
10.506
−23.071
12.004
1.00
54.50
C


ATOM
3813
C
LEU
A
462
7.767
−20.765
9.300
1.00
54.69
C


ATOM
3814
O
LEU
A
462
8.327
−20.740
8.205
1.00
53.99
O


ATOM
3816
N
VAL
A
463
6.569
−21.318
9.512
1.00
54.28
N


ATOM
3817
CA
VAL
A
463
5.796
−21.953
8.465
1.00
53.99
C


ATOM
3819
CB
VAL
A
463
4.410
−22.461
8.975
1.00
54.39
C


ATOM
3821
CG1
VAL
A
463
3.542
−22.982
7.826
1.00
53.31
C


ATOM
3825
CG2
VAL
A
463
4.562
−23.557
10.041
1.00
53.72
C


ATOM
3829
C
VAL
A
463
5.601
−20.961
7.348
1.00
54.63
C


ATOM
3830
O
VAL
A
463
5.741
−21.314
6.190
1.00
54.51
O


ATOM
3832
N
LYS
A
464
5.304
−19.703
7.680
1.00
55.63
N


ATOM
3833
CA
LYS
A
464
5.107
−18.672
6.631
1.00
55.86
C


ATOM
3835
CB
LYS
A
464
4.630
−17.324
7.209
1.00
56.28
C


ATOM
3838
CG
LYS
A
464
3.121
−17.253
7.565
1.00
58.04
C


ATOM
3841
CD
LYS
A
464
2.672
−15.827
8.009
1.00
60.49
C


ATOM
3844
CE
LYS
A
464
1.194
−15.810
8.509
1.00
62.97
C


ATOM
3847
NZ
LYS
A
464
0.561
−14.437
8.612
1.00
63.20
N


ATOM
3851
C
LYS
A
464
6.387
−18.448
5.846
1.00
55.30
C


ATOM
3852
O
LYS
A
464
6.339
−18.187
4.659
1.00
56.07
O


ATOM
3854
N
LYS
A
465
7.538
−18.553
6.501
1.00
54.46
N


ATOM
3855
CA
LYS
A
465
8.811
−18.250
5.828
1.00
53.72
C


ATOM
3857
CB
LYS
A
465
9.857
−17.751
6.842
1.00
54.01
C


ATOM
3860
CG
LYS
A
465
9.795
−16.201
7.084
1.00
55.87
C


ATOM
3863
CD
LYS
A
465
9.944
−15.840
8.581
1.00
58.67
C


ATOM
3866
CE
LYS
A
465
10.260
−14.350
8.860
1.00
57.68
C


ATOM
3869
NZ
LYS
A
465
10.588
−14.212
10.311
1.00
57.74
N


ATOM
3873
C
LYS
A
465
9.326
−19.428
4.987
1.00
52.49
C


ATOM
3874
O
LYS
A
465
10.194
−19.237
4.119
1.00
51.40
O


ATOM
3876
N
LEU
A
466
8.768
−20.624
5.226
1.00
50.63
N


ATOM
3877
CA
LEU
A
466
9.101
−21.806
4.436
1.00
49.58
C


ATOM
3879
CB
LEU
A
466
9.087
−23.089
5.287
1.00
49.23
C


ATOM
3882
CG
LEU
A
466
10.213
−23.203
6.313
1.00
48.53
C


ATOM
3884
CD1
LEU
A
466
9.963
−24.308
7.293
1.00
48.55
C


ATOM
3888
CD2
LEU
A
466
11.526
−23.424
5.651
1.00
48.08
C


ATOM
3892
C
LEU
A
466
8.151
−21.944
3.256
1.00
49.24
C


ATOM
3893
O
LEU
A
466
8.546
−22.426
2.181
1.00
48.61
O


ATOM
3895
N
LEU
A
467
6.905
−21.513
3.436
1.00
48.81
N


ATOM
3896
CA
LEU
A
467
5.935
−21.594
2.361
1.00
48.58
C


ATOM
3898
CB
LEU
A
467
4.551
−21.966
2.901
1.00
48.50
C


ATOM
3901
CG
LEU
A
467
4.379
−23.326
3.599
1.00
48.69
C


ATOM
3903
CD1
LEU
A
467
2.907
−23.533
3.954
1.00
47.86
C


ATOM
3907
CD2
LEU
A
467
4.860
−24.500
2.770
1.00
46.46
C


ATOM
3911
C
LEU
A
467
5.926
−20.279
1.583
1.00
48.49
C


ATOM
3912
O
LEU
A
467
4.879
−19.673
1.380
1.00
48.93
O


ATOM
3914
N
VAL
A
468
7.109
−19.863
1.132
1.00
48.45
N


ATOM
3915
CA
VAL
A
468
7.279
−18.721
0.251
1.00
48.04
C


ATOM
3917
CB
VAL
A
468
8.515
−17.865
0.654
1.00
48.13
C


ATOM
3919
CG1
VAL
A
468
8.954
−16.935
−0.505
1.00
47.61
C


ATOM
3923
CG2
VAL
A
468
8.218
−17.082
1.914
1.00
46.10
C


ATOM
3927
C
VAL
A
468
7.462
−19.201
−1.175
1.00
48.34
C


ATOM
3928
O
VAL
A
468
8.329
−20.017
−1.458
1.00
48.69
O


ATOM
3930
N
VAL
A
469
6.678
−18.621
−2.072
1.00
48.54
N


ATOM
3931
CA
VAL
A
469
6.613
−19.004
−3.475
1.00
48.12
C


ATOM
3933
CB
VAL
A
469
5.482
−18.191
−4.166
1.00
48.00
C


ATOM
3935
CG1
VAL
A
469
5.635
−18.162
−5.673
1.00
45.59
C


ATOM
3939
CG2
VAL
A
469
4.118
−18.783
−3.726
1.00
47.99
C


ATOM
3943
C
VAL
A
469
7.941
−18.846
−4.206
1.00
48.45
C


ATOM
3944
O
VAL
A
469
8.299
−19.681
−5.053
1.00
49.04
O


ATOM
3946
N
ASP
A
470
8.668
−17.787
−3.879
1.00
47.94
N


ATOM
3947
CA
ASP
A
470
9.948
−17.471
−4.528
1.00
47.53
C


ATOM
3949
CB
ASP
A
470
10.259
−15.998
−4.266
1.00
47.37
C


ATOM
3952
CG
ASP
A
470
11.530
−15.552
−4.880
1.00
47.86
C


ATOM
3953
OD1
ASP
A
470
12.318
−16.359
−5.405
1.00
50.10
O


ATOM
3954
OD2
ASP
A
470
11.754
−14.340
−4.842
1.00
54.22
O


ATOM
3955
C
ASP
A
470
11.084
−18.318
−3.937
1.00
47.15
C


ATOM
3956
O
ASP
A
470
11.487
−18.091
−2.799
1.00
46.88
O


ATOM
3958
N
PRO
A
471
11.638
−19.256
−4.721
1.00
46.92
N


ATOM
3959
CA
PRO
A
471
12.618
−20.176
−4.132
1.00
46.91
C


ATOM
3961
CB
PRO
A
471
12.965
−21.144
−5.286
1.00
47.03
C


ATOM
3964
CG
PRO
A
471
12.547
−20.457
−6.549
1.00
47.10
C


ATOM
3967
CD
PRO
A
471
11.489
−19.436
−6.181
1.00
47.26
C


ATOM
3970
C
PRO
A
471
13.868
−19.475
−3.584
1.00
47.02
C


ATOM
3971
O
PRO
A
471
14.478
−19.987
−2.638
1.00
47.05
O


ATOM
3972
N
LYS
A
472
14.229
−18.320
−4.155
1.00
46.81
N


ATOM
3973
CA
LYS
A
472
15.402
−17.575
−3.718
1.00
46.47
C


ATOM
3975
CB
LYS
A
472
15.877
−16.588
−4.779
1.00
46.68
C


ATOM
3978
CG
LYS
A
472
16.300
−17.258
−6.066
1.00
48.98
C


ATOM
3981
CD
LYS
A
472
16.899
−16.286
−7.067
1.00
49.15
C


ATOM
3984
CE
LYS
A
472
18.319
−15.960
−6.668
1.00
51.37
C


ATOM
3987
NZ
LYS
A
472
19.011
−15.193
−7.758
1.00
53.15
N


ATOM
3991
C
LYS
A
472
15.143
−16.826
−2.440
1.00
45.81
C


ATOM
3992
O
LYS
A
472
16.080
−16.585
−1.704
1.00
46.33
O


ATOM
3994
N
ALA
A
473
13.898
−16.456
−2.166
1.00
45.22
N


ATOM
3995
CA
ALA
A
473
13.549
−15.822
−0.887
1.00
44.97
C


ATOM
3997
CB
ALA
A
473
12.351
−14.869
−1.060
1.00
44.55
C


ATOM
4001
C
ALA
A
473
13.230
−16.870
0.181
1.00
44.94
C


ATOM
4002
O
ALA
A
473
13.308
−16.595
1.367
1.00
45.69
O


ATOM
4004
N
ARG
A
474
12.874
−18.086
−0.226
1.00
44.43
N


ATOM
4005
CA
ARG
A
474
12.497
−19.110
0.746
1.00
43.55
C


ATOM
4007
CB
ARG
A
474
12.221
−20.452
0.045
1.00
43.23
C


ATOM
4010
CG
ARG
A
474
11.536
−21.478
0.938
1.00
43.06
C


ATOM
4013
CD
ARG
A
474
10.890
−22.654
0.169
1.00
45.19
C


ATOM
4016
NE
ARG
A
474
10.131
−22.211
−1.004
1.00
44.70
N


ATOM
4018
CZ
ARG
A
474
10.290
−22.677
−2.236
1.00
45.05
C


ATOM
4019
NH1
ARG
A
474
11.139
−23.674
−2.509
1.00
45.04
N


ATOM
4022
NH2
ARG
A
474
9.569
−22.152
−3.206
1.00
45.27
N


ATOM
4025
C
ARG
A
474
13.575
−19.305
1.794
1.00
43.28
C


ATOM
4026
O
ARG
A
474
14.768
−19.237
1.494
1.00
42.80
O


ATOM
4028
N
PHE
A
475
13.153
−19.605
3.011
1.00
43.08
N


ATOM
4029
CA
PHE
A
475
14.090
−19.913
4.062
1.00
43.61
C


ATOM
4031
CB
PHE
A
475
13.376
−20.060
5.412
1.00
43.68
C


ATOM
4034
CG
PHE
A
475
13.542
−18.865
6.330
1.00
45.19
C


ATOM
4035
CD1
PHE
A
475
13.550
−17.550
5.831
1.00
47.37
C


ATOM
4037
CE1
PHE
A
475
13.701
−16.443
6.707
1.00
47.15
C


ATOM
4039
CZ
PHE
A
475
13.850
−16.652
8.071
1.00
45.77
C


ATOM
4041
CE2
PHE
A
475
13.845
−17.942
8.576
1.00
46.83
C


ATOM
4043
CD2
PHE
A
475
13.682
−19.045
7.709
1.00
47.18
C


ATOM
4045
C
PHE
A
475
14.941
−21.147
3.758
1.00
44.21
C


ATOM
4046
O
PHE
A
475
14.459
−22.188
3.267
1.00
43.61
O


ATOM
4048
N
THR
A
476
16.231
−21.012
4.046
1.00
44.74
N


ATOM
4049
CA
THR
A
476
17.126
−22.150
3.984
1.00
45.20
C


ATOM
4051
CB
THR
A
476
18.583
−21.716
3.838
1.00
45.28
C


ATOM
4053
OG1
THR
A
476
18.951
−20.951
4.996
1.00
44.24
O


ATOM
4055
CG2
THR
A
476
18.766
−20.917
2.554
1.00
42.77
C


ATOM
4059
C
THR
A
476
16.975
−22.926
5.280
1.00
46.22
C


ATOM
4060
O
THR
A
476
16.265
−22.493
6.186
1.00
46.18
O


ATOM
4062
N
THR
A
477
17.618
−24.088
5.351
1.00
47.15
N


ATOM
4063
CA
THR
A
477
17.693
−24.842
6.586
1.00
48.13
C


ATOM
4065
CB
THR
A
477
18.396
−26.216
6.390
1.00
48.11
C


ATOM
4067
OG1
THR
A
477
19.559
−26.053
5.570
1.00
49.36
O


ATOM
4069
CG2
THR
A
477
17.490
−27.200
5.695
1.00
47.76
C


ATOM
4073
C
THR
A
477
18.418
−23.991
7.628
1.00
49.12
C


ATOM
4074
O
THR
A
477
17.972
−23.893
8.757
1.00
49.32
O


ATOM
4076
N
GLU
A
478
19.506
−23.331
7.248
1.00
50.57
N


ATOM
4077
CA
GLU
A
478
20.275
−22.532
8.225
1.00
51.68
C


ATOM
4079
CB
GLU
A
478
21.537
−21.917
7.591
1.00
52.02
C


ATOM
4082
CG
GLU
A
478
22.740
−22.885
7.418
1.00
54.69
C


ATOM
4085
CD
GLU
A
478
22.641
−23.882
6.200
1.00
59.11
C


ATOM
4086
OE1
GLU
A
478
21.904
−23.604
5.199
1.00
57.86
O


ATOM
4087
OE2
GLU
A
478
23.324
−24.958
6.280
1.00
59.87
O


ATOM
4088
C
GLU
A
478
19.396
−21.444
8.879
1.00
51.84
C


ATOM
4089
O
GLU
A
478
19.387
−21.293
10.110
1.00
51.67
O


ATOM
4091
N
GLU
A
479
18.641
−20.724
8.047
1.00
51.84
N


ATOM
4092
CA
GLU
A
479
17.715
−19.689
8.519
1.00
51.52
C


ATOM
4094
CB
GLU
A
479
17.113
−18.953
7.336
1.00
51.17
C


ATOM
4097
CG
GLU
A
479
18.121
−18.153
6.488
1.00
51.34
C


ATOM
4100
CD
GLU
A
479
17.453
−17.515
5.282
1.00
52.15
C


ATOM
4101
OE1
GLU
A
479
17.025
−18.244
4.356
1.00
50.84
O


ATOM
4102
OE2
GLU
A
479
17.319
−16.279
5.280
1.00
52.68
O


ATOM
4103
C
GLU
A
479
16.584
−20.238
9.398
1.00
52.20
C


ATOM
4104
O
GLU
A
479
16.100
−19.532
10.300
1.00
52.47
O


ATOM
4106
N
ALA
A
480
16.151
−21.473
9.128
1.00
52.01
N


ATOM
4107
CA
ALA
A
480
15.097
−22.106
9.914
1.00
52.26
C


ATOM
4109
CB
ALA
A
480
14.598
−23.356
9.227
1.00
51.60
C


ATOM
4113
C
ALA
A
480
15.634
−22.448
11.304
1.00
53.02
C


ATOM
4114
O
ALA
A
480
14.976
−22.224
12.320
1.00
52.62
O


ATOM
4116
N
LEU
A
481
16.848
−22.981
11.321
1.00
54.43
N


ATOM
4117
CA
LEU
A
481
17.526
−23.421
12.540
1.00
55.43
C


ATOM
4119
CB
LEU
A
481
18.855
−24.097
12.179
1.00
54.98
C


ATOM
4122
CG
LEU
A
481
19.001
−25.614
12.189
1.00
54.85
C


ATOM
4124
CD1
LEU
A
481
17.706
−26.346
12.368
1.00
55.30
C


ATOM
4128
CD2
LEU
A
481
19.727
−26.066
10.926
1.00
54.39
C


ATOM
4132
C
LEU
A
481
17.802
−22.257
13.494
1.00
57.12
C


ATOM
4133
O
LEU
A
481
17.926
−22.479
14.708
1.00
57.74
O


ATOM
4135
N
ARG
A
482
17.921
−21.041
12.943
1.00
58.35
N


ATOM
4136
CA
ARG
A
482
18.126
−19.820
13.734
1.00
59.67
C


ATOM
4138
CB
ARG
A
482
19.108
−18.889
13.036
1.00
59.60
C


ATOM
4141
CG
ARG
A
482
20.494
−19.484
12.938
1.00
62.22
C


ATOM
4144
CD
ARG
A
482
21.452
−18.444
12.468
1.00
65.02
C


ATOM
4147
NE
ARG
A
482
20.943
−17.800
11.258
1.00
68.45
N


ATOM
4149
CZ
ARG
A
482
21.459
−17.936
10.031
1.00
71.42
C


ATOM
4150
NH1
ARG
A
482
22.546
−18.691
9.804
1.00
72.48
N


ATOM
4153
NH2
ARG
A
482
20.891
−17.285
9.016
1.00
71.66
N


ATOM
4156
C
ARG
A
482
16.845
−19.030
14.003
1.00
60.27
C


ATOM
4157
O
ARG
A
482
16.874
−18.029
14.716
1.00
61.13
O


ATOM
4159
N
HIS
A
483
15.729
−19.450
13.429
1.00
60.43
N


ATOM
4160
CA
HIS
A
483
14.482
−18.781
13.708
1.00
60.79
C


ATOM
4162
CB
HIS
A
483
13.373
−19.438
12.905
1.00
60.56
C


ATOM
4165
CG
HIS
A
483
12.052
−18.755
13.024
1.00
59.44
C


ATOM
4166
ND1
HIS
A
483
11.186
−18.997
14.066
1.00
59.23
N


ATOM
4168
CE1
HIS
A
483
10.094
−18.269
13.907
1.00
58.54
C


ATOM
4170
NE2
HIS
A
483
10.219
−17.570
12.794
1.00
57.64
N


ATOM
4172
CD2
HIS
A
483
11.438
−17.853
12.224
1.00
58.36
C


ATOM
4174
C
HIS
A
483
14.179
−18.831
15.224
1.00
61.36
C


ATOM
4175
O
HIS
A
483
14.520
−19.803
15.902
1.00
61.83
O


ATOM
4177
N
PRO
A
484
13.542
−17.782
15.763
1.00
61.94
N


ATOM
4178
CA
PRO
A
484
13.269
−17.769
17.207
1.00
62.22
C


ATOM
4180
CB
PRO
A
484
12.334
−16.564
17.370
1.00
62.15
C


ATOM
4183
CG
PRO
A
484
12.697
−15.662
16.260
1.00
61.97
C


ATOM
4186
CD
PRO
A
484
13.093
−16.534
15.110
1.00
61.87
C


ATOM
4189
C
PRO
A
484
12.588
−19.027
17.737
1.00
62.57
C


ATOM
4190
O
PRO
A
484
12.895
−19.466
18.840
1.00
62.82
O


ATOM
4191
N
TRP
A
485
11.696
−19.613
16.943
1.00
62.90
N


ATOM
4192
CA
TRP
A
485
10.934
−20.777
17.370
1.00
63.04
C


ATOM
4194
CB
TRP
A
485
9.919
−21.171
16.311
1.00
62.97
C


ATOM
4197
CG
TRP
A
485
8.954
−22.214
16.777
1.00
63.14
C


ATOM
4198
CD1
TRP
A
485
8.060
−22.098
17.796
1.00
63.77
C


ATOM
4200
NE1
TRP
A
485
7.319
−23.257
17.921
1.00
62.72
N


ATOM
4202
CE2
TRP
A
485
7.746
−24.155
16.979
1.00
62.42
C


ATOM
4203
CD2
TRP
A
485
8.774
−23.532
16.235
1.00
62.66
C


ATOM
4204
CE3
TRP
A
485
9.373
−24.241
15.193
1.00
61.41
C


ATOM
4206
CZ3
TRP
A
485
8.938
−25.526
14.933
1.00
61.04
C


ATOM
4208
CH2
TRP
A
485
7.916
−26.118
15.696
1.00
61.02
C


ATOM
4210
CZ2
TRP
A
485
7.311
−25.448
16.715
1.00
61.19
C


ATOM
4212
C
TRP
A
485
11.785
−21.987
17.689
1.00
63.38
C


ATOM
4213
O
TRP
A
485
11.326
−22.898
18.370
1.00
63.58
O


ATOM
4215
N
LEU
A
486
13.009
−22.017
17.186
1.00
64.01
N


ATOM
4216
CA
LEU
A
486
13.902
−23.160
17.435
1.00
64.66
C


ATOM
4218
CB
LEU
A
486
14.529
−23.648
16.107
1.00
64.75
C


ATOM
4221
CG
LEU
A
486
13.598
−24.560
15.304
1.00
64.10
C


ATOM
4223
CD1
LEU
A
486
13.717
−24.300
13.846
1.00
64.50
C


ATOM
4227
CD2
LEU
A
486
13.890
−26.009
15.607
1.00
64.61
C


ATOM
4231
C
LEU
A
486
14.990
−22.849
18.459
1.00
64.90
C


ATOM
4232
O
LEU
A
486
15.809
−23.704
18.769
1.00
64.60
O


ATOM
4234
N
GLN
A
487
15.004
−21.624
18.968
1.00
65.83
N


ATOM
4235
CA
GLN
A
487
15.932
−21.242
20.030
1.00
66.59
C


ATOM
4237
CB
GLN
A
487
16.223
−19.732
19.979
1.00
66.60
C


ATOM
4240
CG
GLN
A
487
16.773
−19.243
18.639
1.00
67.73
C


ATOM
4243
CD
GLN
A
487
17.667
−20.268
17.945
1.00
69.74
C


ATOM
4244
OE1
GLN
A
487
17.422
−20.647
16.798
1.00
72.17
O


ATOM
4245
NE2
GLN
A
487
18.685
−20.738
18.646
1.00
70.27
N


ATOM
4248
C
GLN
A
487
15.295
−21.657
21.352
1.00
66.71
C


ATOM
4249
O
GLN
A
487
14.732
−20.844
22.075
1.00
66.47
O


ATOM
4251
N
ASP
A
488
15.361
−22.948
21.629
1.00
67.26
N


ATOM
4252
CA
ASP
A
488
14.606
−23.547
22.717
1.00
68.10
C


ATOM
4254
CB
ASP
A
488
13.277
−24.113
22.207
1.00
67.46
C


ATOM
4257
CG
ASP
A
488
12.577
−24.967
23.238
1.00
66.84
C


ATOM
4258
OD1
ASP
A
488
13.278
−25.497
24.133
1.00
67.27
O


ATOM
4259
OD2
ASP
A
488
11.334
−25.125
23.158
1.00
63.47
O


ATOM
4260
C
ASP
A
488
15.469
−24.626
23.346
1.00
69.19
C


ATOM
4261
O
ASP
A
488
15.568
−25.750
22.830
1.00
70.05
O


ATOM
4263
N
GLU
A
489
16.090
−24.279
24.469
1.00
70.21
N


ATOM
4264
CA
GLU
A
489
17.151
−25.106
25.056
1.00
70.94
C


ATOM
4266
CB
GLU
A
489
17.942
−24.281
26.060
1.00
71.59
C


ATOM
4269
CG
GLU
A
489
18.630
−23.100
25.374
1.00
74.55
C


ATOM
4272
CD
GLU
A
489
19.389
−23.531
24.118
1.00
77.87
C


ATOM
4273
OE1
GLU
A
489
20.248
−24.441
24.254
1.00
80.21
O


ATOM
4274
OE2
GLU
A
489
19.115
−22.987
23.007
1.00
79.77
O


ATOM
4275
C
GLU
A
489
16.674
−26.402
25.683
1.00
70.35
C


ATOM
4276
O
GLU
A
489
17.454
−27.348
25.816
1.00
70.28
O


ATOM
4278
N
ASP
A
490
15.396
−26.452
26.038
1.00
69.71
N


ATOM
4279
CA
ASP
A
490
14.819
−27.667
26.576
1.00
69.50
C


ATOM
4281
CB
ASP
A
490
13.514
−27.366
27.286
1.00
69.80
C


ATOM
4284
CG
ASP
A
490
13.740
−26.850
28.669
1.00
70.54
C


ATOM
4285
OD1
ASP
A
490
14.854
−27.113
29.212
1.00
68.71
O


ATOM
4286
OD2
ASP
A
490
12.809
−26.183
29.189
1.00
71.34
O


ATOM
4287
C
ASP
A
490
14.565
−28.687
25.514
1.00
68.81
C


ATOM
4288
O
ASP
A
490
14.719
−29.892
25.755
1.00
68.52
O


ATOM
4290
N
MET
A
491
14.138
−28.202
24.349
1.00
68.04
N


ATOM
4291
CA
MET
A
491
13.960
−29.065
23.187
1.00
67.04
C


ATOM
4293
CB
MET
A
491
13.291
−28.294
22.041
1.00
66.35
C


ATOM
4296
CG
MET
A
491
13.141
−29.089
20.745
1.00
64.41
C


ATOM
4299
SD
MET
A
491
14.660
−29.085
19.787
1.00
58.47
S


ATOM
4300
CE
MET
A
491
14.641
−27.415
19.143
1.00
54.91
C


ATOM
4304
C
MET
A
491
15.328
−29.648
22.789
1.00
67.12
C


ATOM
4305
O
MET
A
491
15.471
−30.876
22.678
1.00
65.64
O


ATOM
4307
N
LYS
A
492
16.326
−28.772
22.626
1.00
67.40
N


ATOM
4308
CA
LYS
A
492
17.682
−29.212
22.272
1.00
68.42
C


ATOM
4310
CB
LYS
A
492
18.628
−28.025
22.089
1.00
68.08
C


ATOM
4313
CG
LYS
A
492
18.265
−27.206
20.845
1.00
68.30
C


ATOM
4316
CD
LYS
A
492
19.314
−26.175
20.455
1.00
68.05
C


ATOM
4319
CE
LYS
A
492
18.899
−25.394
19.209
1.00
67.32
C


ATOM
4322
NZ
LYS
A
492
19.448
−24.017
19.226
1.00
66.78
N


ATOM
4326
C
LYS
A
492
18.252
−30.226
23.261
1.00
69.48
C


ATOM
4327
O
LYS
A
492
18.806
−31.260
22.835
1.00
70.01
O


ATOM
4329
N
ARG
A
493
18.078
−29.968
24.564
1.00
70.30
N


ATOM
4330
CA
ARG
A
493
18.545
−30.904
25.587
1.00
70.84
C


ATOM
4332
CB
ARG
A
493
18.272
−30.394
27.000
1.00
71.56
C


ATOM
4335
CG
ARG
A
493
19.413
−29.581
27.588
1.00
73.55
C


ATOM
4338
CD
ARG
A
493
19.540
−29.831
29.088
1.00
76.82
C


ATOM
4341
NE
ARG
A
493
20.205
−31.112
29.363
1.00
79.27
N


ATOM
4343
CZ
ARG
A
493
20.367
−31.651
30.575
1.00
79.48
C


ATOM
4344
NH1
ARG
A
493
19.896
−31.037
31.665
1.00
79.97
N


ATOM
4347
NH2
ARG
A
493
20.989
−32.827
30.694
1.00
78.56
N


ATOM
4350
C
ARG
A
493
17.890
−32.252
25.412
1.00
70.38
C


ATOM
4351
O
ARG
A
493
18.574
−33.265
25.283
1.00
70.23
O


ATOM
4353
N
LYS
A
494
16.563
−32.255
25.402
1.00
70.30
N


ATOM
4354
CA
LYS
A
494
15.791
−33.473
25.122
1.00
70.59
C


ATOM
4356
CB
LYS
A
494
14.318
−33.128
24.867
1.00
70.68
C


ATOM
4359
CG
LYS
A
494
13.376
−34.333
24.823
1.00
72.16
C


ATOM
4362
CD
LYS
A
494
12.796
−34.663
26.207
1.00
74.04
C


ATOM
4365
CE
LYS
A
494
12.669
−36.183
26.412
1.00
74.64
C


ATOM
4368
NZ
LYS
A
494
11.931
−36.568
27.647
1.00
74.04
N


ATOM
4372
C
LYS
A
494
16.379
−34.247
23.928
1.00
70.62
C


ATOM
4373
O
LYS
A
494
16.455
−35.485
23.960
1.00
70.72
O


ATOM
4375
N
PHE
A
495
16.812
−33.510
22.895
1.00
70.46
N


ATOM
4376
CA
PHE
A
495
17.428
−34.115
21.710
1.00
70.24
C


ATOM
4378
CB
PHE
A
495
17.567
−33.099
20.544
1.00
70.06
C


ATOM
4381
CG
PHE
A
495
18.370
−33.625
19.367
1.00
67.41
C


ATOM
4382
CD1
PHE
A
495
17.906
−34.706
18.621
1.00
65.85
C


ATOM
4384
CE1
PHE
A
495
18.643
−35.209
17.567
1.00
65.61
C


ATOM
4386
CZ
PHE
A
495
19.863
−34.617
17.243
1.00
65.54
C


ATOM
4388
CE2
PHE
A
495
20.338
−33.543
17.990
1.00
64.19
C


ATOM
4390
CD2
PHE
A
495
19.596
−33.060
19.036
1.00
65.09
C


ATOM
4392
C
PHE
A
495
18.782
−34.740
22.045
1.00
70.63
C


ATOM
4393
O
PHE
A
495
18.995
−35.926
21.796
1.00
69.99
O


ATOM
4395
N
GLN
A
496
19.690
−33.947
22.600
1.00
71.49
N


ATOM
4396
CA
GLN
A
496
20.982
−34.484
23.018
1.00
72.40
C


ATOM
4398
CB
GLN
A
496
21.808
−33.428
23.740
1.00
72.53
C


ATOM
4401
CG
GLN
A
496
22.297
−32.298
22.833
1.00
73.47
C


ATOM
4404
CD
GLN
A
496
23.076
−32.803
21.604
1.00
74.99
C


ATOM
4405
OE1
GLN
A
496
23.763
−33.825
21.650
1.00
74.06
O


ATOM
4406
NE2
GLN
A
496
22.960
−32.076
20.501
1.00
75.88
N


ATOM
4409
C
GLN
A
496
20.846
−35.736
23.891
1.00
73.06
C


ATOM
4410
O
GLN
A
496
21.618
−36.677
23.724
1.00
73.38
O


ATOM
4412
N
ASP
A
497
19.857
−35.772
24.785
1.00
73.69
N


ATOM
4413
CA
ASP
A
497
19.718
−36.909
25.712
1.00
74.44
C


ATOM
4415
CB
ASP
A
497
18.746
−36.598
26.861
1.00
74.35
C


ATOM
4418
CG
ASP
A
497
19.254
−35.514
27.795
1.00
74.27
C


ATOM
4419
OD1
ASP
A
497
20.456
−35.145
27.753
1.00
73.03
O


ATOM
4420
OD2
ASP
A
497
18.421
−35.018
28.578
1.00
75.36
O


ATOM
4421
C
ASP
A
497
19.253
−38.171
25.012
1.00
74.93
C


ATOM
4422
O
ASP
A
497
19.597
−39.280
25.427
1.00
75.19
O


ATOM
4424
N
LEU
A
498
18.446
−38.002
23.973
1.00
75.54
N


ATOM
4425
CA
LEU
A
498
17.981
−39.128
23.170
1.00
76.01
C


ATOM
4427
CB
LEU
A
498
16.849
−38.671
22.253
1.00
75.95
C


ATOM
4430
CG
LEU
A
498
15.551
−38.314
22.975
1.00
75.90
C


ATOM
4432
CD1
LEU
A
498
14.804
−37.272
22.158
1.00
75.55
C


ATOM
4436
CD2
LEU
A
498
14.682
−39.564
23.248
1.00
73.60
C


ATOM
4440
C
LEU
A
498
19.112
−39.720
22.338
1.00
76.40
C


ATOM
4441
O
LEU
A
498
19.159
−40.925
22.063
1.00
75.87
O


ATOM
4443
N
LEU
A
499
20.021
−38.841
21.947
1.00
77.51
N


ATOM
4444
CA
LEU
A
499
21.151
−39.199
21.116
1.00
78.52
C


ATOM
4446
CB
LEU
A
499
21.860
−37.930
20.643
1.00
78.41
C


ATOM
4449
CG
LEU
A
499
22.442
−37.978
19.234
1.00
79.16
C


ATOM
4451
CD1
LEU
A
499
22.830
−36.554
18.820
1.00
78.37
C


ATOM
4455
CD2
LEU
A
499
23.638
−38.946
19.128
1.00
78.96
C


ATOM
4459
C
LEU
A
499
22.108
−40.091
21.901
1.00
79.42
C


ATOM
4460
O
LEU
A
499
22.387
−41.228
21.490
1.00
79.48
O


ATOM
4462
N
SER
A
500
22.587
−39.579
23.037
1.00
80.45
N


ATOM
4463
CA
SER
A
500
23.525
−40.323
23.882
1.00
81.37
C


ATOM
4465
CB
SER
A
500
24.042
−39.460
25.041
1.00
81.46
C


ATOM
4468
OG
SER
A
500
23.151
−38.407
25.351
1.00
81.99
O


ATOM
4470
C
SER
A
500
22.933
−41.645
24.387
1.00
81.96
C


ATOM
4471
O
SER
A
500
23.653
−42.636
24.519
1.00
81.83
O


ATOM
4473
N
GLU
A
501
21.629
−41.678
24.627
1.00
82.78
N


ATOM
4474
CA
GLU
A
501
20.989
−42.923
25.021
1.00
83.87
C


ATOM
4476
CB
GLU
A
501
19.624
−42.667
25.693
1.00
84.11
C


ATOM
4479
CG
GLU
A
501
18.410
−42.633
24.764
1.00
85.36
C


ATOM
4482
CD
GLU
A
501
17.082
−42.555
25.518
1.00
86.97
C


ATOM
4483
OE1
GLU
A
501
17.091
−42.114
26.695
1.00
86.99
O


ATOM
4484
OE2
GLU
A
501
16.034
−42.932
24.928
1.00
87.22
O


ATOM
4485
C
GLU
A
501
20.891
−43.934
23.853
1.00
84.48
C


ATOM
4486
O
GLU
A
501
20.897
−45.145
24.084
1.00
84.45
O


ATOM
4488
N
GLU
A
502
20.806
−43.460
22.610
1.00
85.32
N


ATOM
4489
CA
GLU
A
502
20.843
−44.384
21.464
1.00
85.98
C


ATOM
4491
CB
GLU
A
502
20.445
−43.697
20.148
1.00
85.98
C


ATOM
4494
CG
GLU
A
502
20.202
−44.689
18.964
1.00
86.01
C


ATOM
4497
CD
GLU
A
502
20.561
−44.115
17.577
1.00
86.02
C


ATOM
4498
OE1
GLU
A
502
21.538
−43.347
17.479
1.00
85.46
O


ATOM
4499
OE2
GLU
A
502
19.872
−44.439
16.575
1.00
85.60
O


ATOM
4500
C
GLU
A
502
22.226
−45.034
21.296
1.00
86.54
C


ATOM
4501
O
GLU
A
502
22.302
−46.201
20.932
1.00
86.75
O


ATOM
4503
N
ASN
A
503
23.303
−44.289
21.561
1.00
87.14
N


ATOM
4504
CA
ASN
A
503
24.665
−44.736
21.215
1.00
87.78
C


ATOM
4506
CB
ASN
A
503
25.574
−43.515
20.958
1.00
88.00
C


ATOM
4509
CG
ASN
A
503
25.167
−42.708
19.717
1.00
88.09
C


ATOM
4510
OD1
ASN
A
503
24.723
−43.261
18.710
1.00
87.51
O


ATOM
4511
ND2
ASN
A
503
25.343
−41.391
19.789
1.00
87.81
N


ATOM
4514
C
ASN
A
503
25.358
−45.676
22.239
1.00
88.06
C


ATOM
4515
O
ASN
A
503
25.685
−45.257
23.356
1.00
87.79
O


ATOM
4517
N
GLU
A
504
25.571
−46.936
21.835
1.00
88.40
N


ATOM
4518
CA
GLU
A
504
26.450
−47.881
22.545
1.00
88.65
C


ATOM
4520
CB
GLU
A
504
25.764
−49.225
22.784
1.00
88.63
C


ATOM
4523
CG
GLU
A
504
25.064
−49.316
24.120
1.00
89.10
C


ATOM
4526
CD
GLU
A
504
24.237
−48.081
24.423
1.00
90.07
C


ATOM
4527
OE1
GLU
A
504
24.810
−47.100
24.941
1.00
90.54
O


ATOM
4528
OE2
GLU
A
504
23.018
−48.091
24.145
1.00
89.81
O


ATOM
4529
C
GLU
A
504
27.731
−48.093
21.750
1.00
88.84
C


ATOM
4530
O
GLU
A
504
27.715
−48.698
20.677
1.00
88.58
O


ATOM
4532
N
SER
A
505
28.837
−47.585
22.296
1.00
89.06
N


ATOM
4533
CA
SER
A
505
30.137
−47.689
21.653
1.00
89.31
C


ATOM
4535
CB
SER
A
505
30.253
−46.586
20.601
1.00
89.49
C


ATOM
4538
OG
SER
A
505
29.232
−46.737
19.623
1.00
89.87
O


ATOM
4540
C
SER
A
505
31.336
−47.694
22.654
1.00
89.29
C


ATOM
4541
O
SER
A
505
31.157
−47.640
23.877
1.00
88.82
O


ATOM
4543
N
THR
A
506
32.547
−47.770
22.103
1.00
89.34
N


ATOM
4544
CA
THR
A
506
33.741
−48.215
22.829
1.00
89.44
C


ATOM
4546
CB
THR
A
506
34.850
−48.614
21.802
1.00
89.43
C


ATOM
4548
OG1
THR
A
506
35.013
−47.569
20.837
1.00
90.10
O


ATOM
4550
CG2
THR
A
506
34.458
−49.872
21.042
1.00
89.22
C


ATOM
4554
C
THR
A
506
34.270
−47.210
23.872
1.00
89.29
C


ATOM
4555
O
THR
A
506
33.873
−46.043
23.879
1.00
89.59
O


ATOM
4557
N
ALA
A
507
35.140
−47.677
24.769
1.00
89.27
N


ATOM
4558
CA
ALA
A
507
35.749
−46.813
25.793
1.00
89.21
C


ATOM
4560
CB
ALA
A
507
36.520
−47.653
26.793
1.00
88.97
C


ATOM
4564
C
ALA
A
507
36.661
−45.774
25.136
1.00
89.23
C


ATOM
4565
O
ALA
A
507
37.346
−46.097
24.174
1.00
89.23
O


ATOM
4567
N
LEU
A
508
36.647
−44.530
25.626
1.00
89.36
N


ATOM
4568
CA
LEU
A
508
37.420
−43.426
25.000
1.00
89.51
C


ATOM
4570
CB
LEU
A
508
36.580
−42.128
24.935
1.00
89.25
C


ATOM
4573
CG
LEU
A
508
35.437
−42.081
23.907
1.00
88.97
C


ATOM
4575
CD1
LEU
A
508
34.213
−42.865
24.385
1.00
88.65
C


ATOM
4579
CD2
LEU
A
508
35.033
−40.659
23.584
1.00
88.54
C


ATOM
4583
C
LEU
A
508
38.765
−43.175
25.738
1.00
89.74
C


ATOM
4584
O
LEU
A
508
38.839
−43.366
26.959
1.00
89.58
O


ATOM
4586
N
PRO
A
509
39.832
−42.756
25.006
1.00
90.02
N


ATOM
4587
CA
PRO
A
509
41.123
−42.594
25.694
1.00
90.13
C


ATOM
4589
CB
PRO
A
509
42.074
−42.158
24.574
1.00
89.89
C


ATOM
4592
CG
PRO
A
509
41.489
−42.754
23.368
1.00
90.03
C


ATOM
4595
CD
PRO
A
509
40.000
−42.630
23.545
1.00
90.03
C


ATOM
4598
C
PRO
A
509
41.117
−41.575
26.838
1.00
90.34
C


ATOM
4599
O
PRO
A
509
40.757
−40.409
26.634
1.00
90.08
O


ATOM
4600
N
GLN
A
510
41.481
−42.065
28.031
1.00
90.54
N


ATOM
4601
CA
GLN
A
510
41.797
−41.251
29.211
1.00
90.53
C


ATOM
4603
CB
GLN
A
510
42.883
−40.218
28.871
1.00
90.54
C


ATOM
4606
CG
GLN
A
510
43.648
−39.669
30.081
1.00
90.88
C


ATOM
4609
CD
GLN
A
510
43.070
−38.366
30.640
1.00
90.95
C


ATOM
4610
OE1
GLN
A
510
42.095
−37.821
30.111
1.00
91.20
O


ATOM
4611
NE2
GLN
A
510
43.681
−37.859
31.712
1.00
90.01
N


ATOM
4614
C
GLN
A
510
40.565
−40.582
29.799
1.00
90.23
C


ATOM
4615
O
GLN
A
510
39.778
−39.990
29.075
1.00
89.98
O


ATOM
4617
CAL
DRG
X
1
6.858
−48.885
9.748
1.00
80.66
C


ATOM
4619
CBA
DRG
X
1
6.408
−49.431
10.970
1.00
81.84
C


ATOM
4620
CAI
DRG
X
1
5.050
−49.567
11.265
1.00
82.72
C


ATOM
4622
CAF
DRG
X
1
4.647
−50.113
12.490
1.00
82.95
C


ATOM
4624
CAW
DRG
X
1
5.608
−50.521
13.418
1.00
82.95
C


ATOM
4625
CAB
DRG
X
1
5.239
−51.068
14.650
1.00
82.53
C


ATOM
4629
NAP
DRG
X
1
6.912
−50.377
13.120
1.00
83.45
N


ATOM
4630
CBC
DRG
X
1
7.320
−49.852
11.942
1.00
82.14
C


ATOM
4631
CAJ
DRG
X
1
8.675
−49.739
11.690
1.00
81.02
C


ATOM
4633
CAG
DRG
X
1
9.124
−49.203
10.485
1.00
80.72
C


ATOM
4635
CAX
DRG
X
1
8.238
−48.758
9.481
1.00
80.00
C


ATOM
4636
NAR
DRG
X
1
8.652
−48.231
8.279
1.00
78.44
N


ATOM
4638
CAV
DRG
X
1
9.980
−48.286
7.857
1.00
75.21
C


ATOM
4639
OAE
DRG
X
1
10.873
−48.829
8.510
1.00
74.14
O


ATOM
4640
CAZ
DRG
X
1
10.305
−47.778
6.633
1.00
73.38
C


ATOM
4641
NAS
DRG
X
1
9.522
−47.076
5.797
1.00
72.70
N


ATOM
4643
CAN
DRG
X
1
11.507
−47.933
6.034
1.00
72.48
C


ATOM
4645
CBB
DRG
X
1
11.472
−47.322
4.841
1.00
70.35
C


ATOM
4646
CAM
DRG
X
1
12.399
−47.194
3.885
1.00
68.99
C


ATOM
4648
CBD
DRG
X
1
10.238
−46.788
4.694
1.00
71.35
C


ATOM
4649
CAK
DRG
X
1
9.904
−46.101
3.588
1.00
70.04
C


ATOM
4651
CAH
DRG
X
1
10.829
−45.944
2.557
1.00
69.73
C


ATOM
4653
CAY
DRG
X
1
12.120
−46.483
2.698
1.00
68.65
C


ATOM
4654
CAU
DRG
X
1
13.062
−46.359
1.655
1.00
65.55
C


ATOM
4655
CAA
DRG
X
1
14.584
−46.485
1.890
1.00
63.40
C


ATOM
4659
NAO
DRG
X
1
12.580
−46.316
0.403
1.00
64.85
N


ATOM
4660
NAQ
DRG
X
1
13.390
−46.274
−0.687
1.00
65.79
N


ATOM
4662
CAT
DRG
X
1
12.771
−46.168
−1.900
1.00
65.39
C


ATOM
4663
NAD
DRG
X
1
13.474
−46.101
−3.044
1.00
64.35
N


ATOM
4666
NAC
DRG
X
1
11.432
−46.108
−1.988
1.00
65.90
N


ATOM
4669
O
HOH
C
1
20.930
−26.484
−5.467
1.00
37.35
O


ATOM
4672
O
HOH
C
2
11.241
−67.537
0.693
1.00
52.17
O


ATOM
4675
O
HOH
C
3
11.866
−13.585
19.362
1.00
66.67
O


ATOM
4678
O
HOH
C
4
21.551
−24.045
2.097
1.00
53.00
O


ATOM
4681
O
HOH
C
5
15.849
−68.979
−1.703
1.00
47.22
O


ATOM
4684
O
HOH
C
6
19.141
−25.650
2.896
1.00
41.05
O


ATOM
4687
O
HOH
C
7
15.162
−48.681
−10.570
1.00
77.34
O


ATOM
4690
O
HOH
C
8
8.238
−43.990
1.181
1.00
55.79
O


ATOM
4693
O
HOH
C
9
23.345
−32.040
13.063
1.00
45.27
O


ATOM
4696
O
HOH
C
10
5.313
−40.618
25.009
1.00
70.54
O


ATOM
4699
O
HOH
C
11
14.643
−20.120
−18.788
1.00
52.15
O


ATOM
4702
O
HOH
C
12
13.131
−16.510
−7.994
1.00
49.32
O


ATOM
4705
O
HOH
C
13
24.923
−71.081
−1.533
1.00
61.12
O


ATOM
4708
O
HOH
C
14
27.904
−26.745
9.990
1.00
64.30
O


ATOM
4711
O
HOH
C
15
24.202
−45.754
5.931
1.00
60.23
O


ATOM
4714
O
HOH
C
16
11.295
−32.748
−0.676
1.00
47.49
O


ATOM
4717
O
HOH
C
17
5.143
−16.239
−1.389
1.00
49.61
O


ATOM
4720
O
HOH
C
18
14.008
−24.975
−6.302
1.00
44.88
O


ATOM
4723
O
HOH
C
19
24.591
−60.631
9.238
1.00
63.84
O


ATOM
4726
O
HOH
C
20
23.249
−62.769
9.802
1.00
62.08
O


ATOM
4729
O
HOH
C
21
1.344
−44.323
3.749
1.00
57.24
O


ATOM
4732
O
HOH
C
22
14.938
−23.179
−8.497
1.00
48.63
O


ATOM
4735
O
HOH
C
23
12.315
−45.744
−5.727
1.00
62.98
O


ATOM
4738
O
HOH
C
24
−1.044
−20.065
21.638
1.00
67.43
O


ATOM
4741
O
HOH
C
25
7.123
−15.123
−2.722
1.00
50.52
O


ATOM
4744
O
HOH
C
26
22.377
−58.926
−5.005
1.00
69.12
O


ATOM
4747
O
HOH
C
27
17.716
−27.416
29.164
1.00
58.71
O


ATOM
4750
O
HOH
C
28
21.799
−61.267
−4.095
1.00
62.77
O


ATOM
4753
O
HOH
C
29
19.416
−51.379
13.861
1.00
66.09
O


ATOM
4756
O
HOH
C
30
20.031
−29.184
33.548
1.00
51.93
O


ATOM
4759
O
HOH
C
31
7.546
−48.748
−2.331
1.00
66.88
O


ATOM
4762
O
HOH
C
32
8.097
−37.892
−6.319
1.00
66.69
O


ATOM
4765
O
HOH
C
33
16.004
−20.218
−0.585
1.00
48.10
O


ATOM
4768
O
HOH
C
34
17.264
−22.295
−12.830
1.00
60.90
O


ATOM
4771
O
HOH
C
35
2.962
−47.830
6.211
1.00
67.47
O


ATOM
4774
O
HOH
C
36
20.468
−64.851
−3.672
1.00
60.63
O


ATOM
4777
O
HOH
C
37
2.823
−16.881
20.692
1.00
65.77
O


ATOM
4780
O
HOH
C
38
19.443
−55.271
−11.289
1.00
70.17
O


ATOM
4783
O
HOH
C
39
17.373
−14.509
−14.627
1.00
66.09
O


ATOM
4786
O
HOH
C
40
17.414
−12.269
−17.448
1.00
53.14
O


ATOM
4789
O
HOH
C
41
22.605
−66.406
−3.102
1.00
71.61
O


ATOM
4792
O
HOH
C
42
16.408
−16.870
10.741
1.00
49.77
O

## Claims

1. A method of treating an Hepatitis C Virus infection in a patient, comprising providing a therapeutically effective amount, to a patient in need thereof, of a compound of Formula I



or a pharmaceutically acceptable salt thereof, wherein:
G1 is a group of the formula




 where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S, which Het is optionally substituted;
Ar1 is a 6,6-fused or 6,5 bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which An is optionally substituted,
Ar2 is phenyl, a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, or a 6,5 bicyclic aromatic ring system containing 1, 2, or 3, nitrogen atoms, with remaining atoms being carbon, which Ar2 is optionally substituted;
R is a group of the formula —NH(C═O)— or —(O═C)NH—; R3 is hydrogen or C1-C6alkyl;
R3 is taken together with an Ar2 substituent to form a 5- or 6-membered unsaturated or aromatic R3/Ar2 ring having 0, 1, or 2 heteroatoms independently chosen from N, O, and S, which R3/Ar2 ring is optionally substituted;
R4 is hydrogen or C1-C6alkyl;
R5 is amino, —NHOH, or optionally substituted mono- or di-alkylamino, and R6 is hydrogen or hydroxyl; or
R5 and R6 are taken together to form a 5 or 6-membered heterocyclic ring, which is unsaturated or aromatic and which contains 0, 1, or 2 additional heteroatoms chosen from N, S, and O, which 5 or 6-membered heterocyclic ring is optionally substituted.

2. A method of inhibiting Hepatitis C Virus replication comprising contacting the virus with a concentration of a compound sufficient to inhibit Hepatitis C Virus replication in vitro, wherein the compound is a compound of Formula I



or a pharmaceutically acceptable salt thereof, wherein:
G1 is a group of the formula




 where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted;
Ar1 is a 6,6-fused or 6,5 bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which An is optionally substituted,
Ar2 is phenyl, a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, or a 6,5 bicyclic aromatic ring system containing 1, 2, or 3, nitrogen atoms, with remaining atoms being carbon, which Ar2 is optionally substituted;
R is a group of the formula —NH(C═O)— or —(O═C)NH—; R3 is hydrogen or C1-C6alkyl;

R3 is taken together with an Ar2 substituent to form a 5- or 6-membered unsaturated or aromatic R3/Ar2 ring having 0, 1, or 2 heteroatoms independently chosen from N, O, and S, which R3/Ar2 ring is optionally substituted;
R4 is hydrogen or C1-C6alkyl;
R5 is amino, —NHOH, or optionally substituted mono- or dialkylamino, and R6 is hydrogen or hydroxyl; or
R5 and R6 are taken together to form a 5 or 6-membered heterocyclic ring, which is unsaturated or aromatic and which contains 0, 1, or 2 additional heteroatoms chosen from N, S, and O, which 5 or 6-membered heterocyclic ring is optionally substituted.

3. The method of claim 1 wherein the compound of Formula I is administered together with a therapeutically effective amount of at least one additional active agent.

4. The method of claim 3, wherein the additional active agent is an interferon or an anti-HCV agent that is not a compound or salt of Formula I.

5. The method of claim 4, wherein the anti-HCV agent that is not a compound or salt of Formula I is an HCV protease inhibitor, an HCV NS3 inhibitor, and HCV NS4a inhibitor, an HCV NS5a, or an HCV NS5b inhibitor.

6. The method of claim 1, wherein R is —NH(C═O)—.

7. The method of claim 1, wherein R is —(C═O)NH—.

8. The method of claim 1, wherein G1 is a group of the formula

9. The method of claim 1, wherein G1 is a group of the formula




where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted.

10. The method of claim 9 where n is 0 or 1 and Het is an optionally substituted imidazolyl group.

11. The method of claim 1, wherein
Ar1 and Ar1 are independently chosen from quinolinyl, isoquinolinyl, benzimidazolyl, indolyl, naphthyl, phenyl, pyridyl, and pyrimidinyl groups, wherein
Ar1 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C3-C7cycloalkyl, 5- to 7-membered heterocycloalkyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; and
Ar2 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, C1-C4alkyl, C1-C4alkoxy, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.

12. The method of claim 11, wherein Ar2 is benzimidazolyl, which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, amino, C1-C2alkyl, C1-C2alkoxy, (mono- or di-C1-C2alkylamino)C0-C2alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.

13. The method of claim 1, wherein the compound or salt of Formula I is a compound of the formula:




where
R1 is absent or is 1 or more substituents bound to either ring of the bicyclic system and independently selected from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, C3-C7cycloalkyl, 5- to 7-membered heterocycloalkyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; and
R2 is absent or is 1 or more substituents independently selected from halogen, hydroxyl, amino, nitro, cyano, —COOH, —CONH2, C1-C6alkyl, C1-C6alkoxy, C2-C6alkanoyl, (mono- or di-C1-C4alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy.

14. The method of claim 13, wherein R3 is methyl, R5 is amino, and R6 is hydrogen.

15. The method of claim 13, wherein R1 is 1 or 2 substituents independently chosen from halogen, nitro, acetyl, C1-C2alkyl, and C1-C2alkoxy.

16. The method of claim 13, wherein R2 is absent.

17. The method of claim 1, wherein the compound is









or a salt of any of the foregoing.

18. A method of treating Hepatitis C Virus infection comprising
(i) informing a patient that a compound of Formula I or a pharmaceutically acceptable salt thereof is useful for treating Hepatitis C Virus infection; and
(ii) providing the compound of Formula I in a container to the patient, wherein the compound of Formula I is




or a pharmaceutically acceptable salt thereof, wherein:
G1 is a group of the formula




 where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S; which Het is optionally substituted;
Ar1 is a 6,6-fused or 6,5 bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which An is optionally substituted,
Ar2 is phenyl, a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, or a 6,5 bicyclic aromatic ring system containing 1, 2, or 3, nitrogen atoms, with remaining atoms being carbon, which Ar2 is optionally substituted;
R is a group of the formula —NH(C═O)— or —(O═C)NH—; R3 is hydrogen or C1-C6alkyl;
R3 is taken together with an Ar2 substituent to form a 5- or 6-membered unsaturated or aromatic R3/Ar2 ring having 0, 1, or 2 heteroatoms independently chosen from N, O, and S, which R3/Ar2 ring is optionally substituted;
R4 is hydrogen or C1-C6alkyl;
R5 is amino, —NHOH, or optionally substituted mono- or di-alkylamino, and R6 is hydrogen or hydroxyl; or
R5 and R6 are taken together to form a 5 or 6-membered heterocyclic ring, which is unsaturated or aromatic and which contains 0, 1, or 2 additional heteroatoms chosen from N, S, and O, which 5 or 6-membered heterocyclic ring is optionally substituted.

19. The method of claim 1, wherein the compound or salt of Formula I is administered together with another active agent.

20. A crystal comprising a checkpoint kinase 2 in crystalline form, wherein the crystal comprises a chemical entity bound to the active site of the checkpoint kinase 2, wherein the chemical entity comprises a compound of Formula I



or a pharmaceutically acceptable salt thereof, wherein:
G1 is a group of the formula




 where n is 0, 1, 2, 3, or 4 and Het is a 5- or 6-membered heteroaryl group containing 1 to 4 heteroatoms independently chosen from N, O, and S, which Het is optionally substituted;
Ar1 is a 6,6-fused or 6,5 bicyclic aromatic ring system containing only carbon ring atoms or containing 1, 2, or 3 nitrogen ring atoms with remaining atoms being carbon, which An is optionally substituted,
Ar2 is phenyl, a 6-membered heteroaryl ring containing 1 or 2 nitrogen ring atoms, or a 6,5 bicyclic aromatic ring system containing 1, 2, or 3, nitrogen atoms, with remaining atoms being carbon, which Ar2 is optionally substituted;
R is a group of the formula —NH(C═O)— or —(O═C)NH—; R3 is hydrogen or C1-C6alkyl;
R3 is taken together with an Ar2 substituent to form a 5- or 6-membered unsaturated or aromatic R3/Ar2 ring having 0, 1, or 2 heteroatoms independently chosen from N, O, and S, which R3/Ar2 ring is optionally substituted;
R4 is hydrogen or C1-C6alkyl;
R5 is amino, —NHOH, or optionally substituted mono- or di-alkylamino, and R6 is hydrogen or hydroxyl; or
R5 and R6 are taken together to form a 5 or 6-membered heterocyclic ring, which is unsaturated or aromatic and which contains 0, 1, or 2 additional heteroatoms chosen from N, S, and O, which 5 or 6-membered heterocyclic ring is optionally substituted.

21. The crystal of claim 20 wherein the chemical entity comprises:









or a salt of any of the foregoing.

22. The crystal of claim 20 wherein the chemical entity comprises:



or a salt thereof.

23. The crystal of claim 20, further comprising a three-dimensional structure wherein the three-dimensional structure comprises atoms and atomic coordinates set forth in Table 2.