HEADER TRANSFERASE/TRANSFERASE INHIBITOR 14-MAR-18 6CPW
TITLE DISCOVERY OF 3(S)-THIOMETHYL PYRROLIDINE ERK INHIBITORS FOR ONCOLOGY
COMPND MOL_ID: 1;
COMPND 2 MOLECULE: MITOGEN-ACTIVATED PROTEIN KINASE 1;
COMPND 3 CHAIN: A;
COMPND 4 SYNONYM: MAPK 1,ERT1,EXTRACELLULAR SIGNAL-REGULATED KINASE 2,ERK-2,
COMPND 5 MAP KINASE ISOFORM P42,P42-MAPK,MITOGEN-ACTIVATED PROTEIN KINASE 2,
COMPND 6 MAPK 2;
COMPND 7 EC: 2.7.11.24;
COMPND 8 ENGINEERED: YES
SOURCE MOL_ID: 1;
SOURCE 2 ORGANISM_SCIENTIFIC: RATTUS NORVEGICUS;
SOURCE 3 ORGANISM_COMMON: RAT;
SOURCE 4 ORGANISM_TAXID: 10116;
SOURCE 5 GENE: MAPK1, ERK2, MAPK, PRKM1;
SOURCE 6 EXPRESSION_SYSTEM: ESCHERICHIA COLI BL21(DE3);
SOURCE 7 EXPRESSION_SYSTEM_TAXID: 469008;
SOURCE 8 EXPRESSION_SYSTEM_STRAIN: BL21(DE3)
KEYWDS TRANSFERASE, SERINE/THREONINE-PROTEIN KINASE, MAP KINASE,
KEYWDS 2 TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
EXPDTA X-RAY DIFFRACTION
AUTHOR A.HRUZA,A.HRUZA
REVDAT 2 30-MAY-18 6CPW 1 JRNL
REVDAT 1 23-MAY-18 6CPW 0
JRNL AUTH S.B.BOGA,A.B.ALHASSAN,A.B.COOPER,R.DOLL,N.Y.SHIH,G.SHIPPS,
JRNL AUTH 2 Y.DENG,H.ZHU,Y.NAN,R.SUN,L.ZHU,J.DESAI,M.PATEL,K.MUPPALLA,
JRNL AUTH 3 X.GAO,J.WANG,X.YAO,J.KELLY,S.GUDIPATI,S.PALIWAL,H.C.TSUI,
JRNL AUTH 4 T.WANG,B.SHERBORNE,L.XIAO,A.HRUZA,A.BUEVICH,L.K.ZHANG,
JRNL AUTH 5 D.HESK,A.A.SAMATAR,D.CARR,B.LONG,S.BLACK,P.DAYANANTH,
JRNL AUTH 6 W.WINDSOR,P.KIRSCHMEIER,R.BISHOP
JRNL TITL DISCOVERY OF 3(S)-THIOMETHYL PYRROLIDINE ERK INHIBITORS FOR
JRNL TITL 2 ONCOLOGY.
JRNL REF BIOORG. MED. CHEM. LETT. V. 28 2029 2018
JRNL REFN ESSN 1464-3405
JRNL PMID 29748051
JRNL DOI 10.1016/J.BMCL.2018.04.063
REMARK 2
REMARK 2 RESOLUTION. 1.85 ANGSTROMS.
REMARK 3
REMARK 3 REFINEMENT.
REMARK 3 PROGRAM : BUSTER 2.11.7
REMARK 3 AUTHORS : BRICOGNE,BLANC,BRANDL,FLENSBURG,KELLER,
REMARK 3 : PACIOREK,ROVERSI,SHARFF,SMART,VONRHEIN,
REMARK 3 : WOMACK,MATTHEWS,TEN EYCK,TRONRUD
REMARK 3
REMARK 3 DATA USED IN REFINEMENT.
REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS) : 1.85
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 33.22
REMARK 3 DATA CUTOFF (SIGMA(F)) : 0.000
REMARK 3 COMPLETENESS FOR RANGE (%) : 99.5
REMARK 3 NUMBER OF REFLECTIONS : 35845
REMARK 3
REMARK 3 FIT TO DATA USED IN REFINEMENT.
REMARK 3 CROSS-VALIDATION METHOD : THROUGHOUT
REMARK 3 FREE R VALUE TEST SET SELECTION : RANDOM
REMARK 3 R VALUE (WORKING + TEST SET) : 0.190
REMARK 3 R VALUE (WORKING SET) : 0.188
REMARK 3 FREE R VALUE : 0.224
REMARK 3 FREE R VALUE TEST SET SIZE (%) : 5.030
REMARK 3 FREE R VALUE TEST SET COUNT : 1803
REMARK 3 ESTIMATED ERROR OF FREE R VALUE : NULL
REMARK 3
REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN.
REMARK 3 TOTAL NUMBER OF BINS USED : 18
REMARK 3 BIN RESOLUTION RANGE HIGH (ANGSTROMS) : 1.85
REMARK 3 BIN RESOLUTION RANGE LOW (ANGSTROMS) : 1.90
REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) : 97.26
REMARK 3 REFLECTIONS IN BIN (WORKING + TEST SET) : 2851
REMARK 3 BIN R VALUE (WORKING + TEST SET) : 0.2009
REMARK 3 REFLECTIONS IN BIN (WORKING SET) : 2702
REMARK 3 BIN R VALUE (WORKING SET) : 0.1989
REMARK 3 BIN FREE R VALUE : 0.2385
REMARK 3 BIN FREE R VALUE TEST SET SIZE (%) : 5.23
REMARK 3 BIN FREE R VALUE TEST SET COUNT : 149
REMARK 3 ESTIMATED ERROR OF BIN FREE R VALUE : NULL
REMARK 3
REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.
REMARK 3 PROTEIN ATOMS : 2684
REMARK 3 NUCLEIC ACID ATOMS : 0
REMARK 3 HETEROGEN ATOMS : 57
REMARK 3 SOLVENT ATOMS : 257
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2) : 25.41
REMARK 3 MEAN B VALUE (OVERALL, A**2) : 31.40
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2) : -5.22850
REMARK 3 B22 (A**2) : 2.27590
REMARK 3 B33 (A**2) : 2.95270
REMARK 3 B12 (A**2) : 0.00000
REMARK 3 B13 (A**2) : 0.00000
REMARK 3 B23 (A**2) : 0.00000
REMARK 3
REMARK 3 ESTIMATED COORDINATE ERROR.
REMARK 3 ESD FROM LUZZATI PLOT (A) : 0.210
REMARK 3 DPI (BLOW EQ-10) BASED ON R VALUE (A) : 0.130
REMARK 3 DPI (BLOW EQ-9) BASED ON FREE R VALUE (A) : 0.123
REMARK 3 DPI (CRUICKSHANK) BASED ON R VALUE (A) : 0.167
REMARK 3 DPI (CRUICKSHANK) BASED ON FREE R VALUE (A) : 0.120
REMARK 3
REMARK 3 REFERENCES: BLOW, D. (2002) ACTA CRYST D58, 792-797
REMARK 3 CRUICKSHANK, D.W.J. (1999) ACTA CRYST D55, 583-601
REMARK 3
REMARK 3 CORRELATION COEFFICIENTS.
REMARK 3 CORRELATION COEFFICIENT FO-FC : 0.935
REMARK 3 CORRELATION COEFFICIENT FO-FC FREE : 0.919
REMARK 3
REMARK 3 NUMBER OF GEOMETRIC FUNCTION TERMS DEFINED : 15
REMARK 3 TERM COUNT WEIGHT FUNCTION.
REMARK 3 BOND LENGTHS : 5527 ; 2.000 ; HARMONIC
REMARK 3 BOND ANGLES : 9987 ; 2.000 ; HARMONIC
REMARK 3 TORSION ANGLES : 1222 ; 2.000 ; SINUSOIDAL
REMARK 3 TRIGONAL CARBON PLANES : 70 ; 2.000 ; HARMONIC
REMARK 3 GENERAL PLANES : 836 ; 5.000 ; HARMONIC
REMARK 3 ISOTROPIC THERMAL FACTORS : 5527 ; 20.000 ; HARMONIC
REMARK 3 BAD NON-BONDED CONTACTS : NULL ; NULL ; NULL
REMARK 3 IMPROPER TORSIONS : NULL ; NULL ; NULL
REMARK 3 PSEUDOROTATION ANGLES : NULL ; NULL ; NULL
REMARK 3 CHIRAL IMPROPER TORSION : 359 ; 5.000 ; SEMIHARMONIC
REMARK 3 SUM OF OCCUPANCIES : NULL ; NULL ; NULL
REMARK 3 UTILITY DISTANCES : NULL ; NULL ; NULL
REMARK 3 UTILITY ANGLES : NULL ; NULL ; NULL
REMARK 3 UTILITY TORSION : NULL ; NULL ; NULL
REMARK 3 IDEAL-DIST CONTACT TERM : 6137 ; 4.000 ; SEMIHARMONIC
REMARK 3
REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES.
REMARK 3 BOND LENGTHS (A) : 0.010
REMARK 3 BOND ANGLES (DEGREES) : 1.01
REMARK 3 PEPTIDE OMEGA TORSION ANGLES (DEGREES) : 3.43
REMARK 3 OTHER TORSION ANGLES (DEGREES) : 14.72
REMARK 3
REMARK 3 TLS DETAILS
REMARK 3 NUMBER OF TLS GROUPS : 1
REMARK 3
REMARK 3 TLS GROUP : 1
REMARK 3 SELECTION: { A|* }
REMARK 3 ORIGIN FOR THE GROUP (A): 53.0927 19.1996 19.9867
REMARK 3 T TENSOR
REMARK 3 T11: -0.0756 T22: -0.0522
REMARK 3 T33: -0.0753 T12: 0.0113
REMARK 3 T13: -0.0042 T23: -0.0051
REMARK 3 L TENSOR
REMARK 3 L11: 1.2754 L22: 0.5999
REMARK 3 L33: 0.9070 L12: -0.4259
REMARK 3 L13: -0.5477 L23: 0.1204
REMARK 3 S TENSOR
REMARK 3 S11: 0.0514 S12: 0.1984 S13: -0.0757
REMARK 3 S21: -0.0227 S22: -0.0686 S23: 0.0788
REMARK 3 S31: -0.0479 S32: -0.0816 S33: 0.0172
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS: NULL
REMARK 4
REMARK 4 6CPW COMPLIES WITH FORMAT V. 3.30, 13-JUL-11
REMARK 100
REMARK 100 THIS ENTRY HAS BEEN PROCESSED BY RCSB ON 16-MAR-18.
REMARK 100 THE DEPOSITION ID IS D_1000233196.
REMARK 200
REMARK 200 EXPERIMENTAL DETAILS
REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION
REMARK 200 DATE OF DATA COLLECTION : 06-SEP-06
REMARK 200 TEMPERATURE (KELVIN) : 95
REMARK 200 PH : 6.4
REMARK 200 NUMBER OF CRYSTALS USED : 1
REMARK 200
REMARK 200 SYNCHROTRON (Y/N) : N
REMARK 200 RADIATION SOURCE : ROTATING ANODE
REMARK 200 BEAMLINE : NULL
REMARK 200 X-RAY GENERATOR MODEL : RIGAKU FR-E SUPERBRIGHT
REMARK 200 MONOCHROMATIC OR LAUE (M/L) : M
REMARK 200 WAVELENGTH OR RANGE (A) : 1.54178
REMARK 200 MONOCHROMATOR : NULL
REMARK 200 OPTICS : OSMIC
REMARK 200
REMARK 200 DETECTOR TYPE : IMAGE PLATE
REMARK 200 DETECTOR MANUFACTURER : RIGAKU RAXIS HTC
REMARK 200 INTENSITY-INTEGRATION SOFTWARE : DENZO
REMARK 200 DATA SCALING SOFTWARE : SCALEPACK
REMARK 200
REMARK 200 NUMBER OF UNIQUE REFLECTIONS : 35845
REMARK 200 RESOLUTION RANGE HIGH (A) : 1.850
REMARK 200 RESOLUTION RANGE LOW (A) : 33.220
REMARK 200 REJECTION CRITERIA (SIGMA(I)) : NULL
REMARK 200
REMARK 200 OVERALL.
REMARK 200 COMPLETENESS FOR RANGE (%) : 99.5
REMARK 200 DATA REDUNDANCY : 4.700
REMARK 200 R MERGE (I) : 0.88000
REMARK 200 R SYM (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : 14.0000
REMARK 200
REMARK 200 IN THE HIGHEST RESOLUTION SHELL.
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.85
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.90
REMARK 200 COMPLETENESS FOR SHELL (%) : 100.0
REMARK 200 DATA REDUNDANCY IN SHELL : 4.60
REMARK 200 R MERGE FOR SHELL (I) : 0.49200
REMARK 200 R SYM FOR SHELL (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR SHELL : 2.900
REMARK 200
REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH
REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: FOURIER SYNTHESIS
REMARK 200 SOFTWARE USED: CNX
REMARK 200 STARTING MODEL: 1ERK
REMARK 200
REMARK 200 REMARK: NULL
REMARK 280
REMARK 280 CRYSTAL
REMARK 280 SOLVENT CONTENT, VS (%): 49.45
REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.43
REMARK 280
REMARK 280 CRYSTALLIZATION CONDITIONS: 0.1M MES, PH 6.4, 2.0M AMMONIUM
REMARK 280 SULFATE, 5% PEG 400, 0.5% DMSO, 1% GLYEROL, 0.0005M OLOMOUCINE.
REMARK 280 13 DAY SOAK WITH NEW COMPOUND AT 500 MICROMOLAR CONCENTRATION,
REMARK 280 VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277K
REMARK 290
REMARK 290 CRYSTALLOGRAPHIC SYMMETRY
REMARK 290 SYMMETRY OPERATORS FOR SPACE GROUP: P 21 21 2
REMARK 290
REMARK 290 SYMOP SYMMETRY
REMARK 290 NNNMMM OPERATOR
REMARK 290 1555 X,Y,Z
REMARK 290 2555 -X,-Y,Z
REMARK 290 3555 -X+1/2,Y+1/2,-Z
REMARK 290 4555 X+1/2,-Y+1/2,-Z
REMARK 290
REMARK 290 WHERE NNN -> OPERATOR NUMBER
REMARK 290 MMM -> TRANSLATION VECTOR
REMARK 290
REMARK 290 CRYSTALLOGRAPHIC SYMMETRY TRANSFORMATIONS
REMARK 290 THE FOLLOWING TRANSFORMATIONS OPERATE ON THE ATOM/HETATM
REMARK 290 RECORDS IN THIS ENTRY TO PRODUCE CRYSTALLOGRAPHICALLY
REMARK 290 RELATED MOLECULES.
REMARK 290 SMTRY1 1 1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 1 0.000000 1.000000 0.000000 0.00000
REMARK 290 SMTRY3 1 0.000000 0.000000 1.000000 0.00000
REMARK 290 SMTRY1 2 -1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 2 0.000000 -1.000000 0.000000 0.00000
REMARK 290 SMTRY3 2 0.000000 0.000000 1.000000 0.00000
REMARK 290 SMTRY1 3 -1.000000 0.000000 0.000000 35.67050
REMARK 290 SMTRY2 3 0.000000 1.000000 0.000000 45.65900
REMARK 290 SMTRY3 3 0.000000 0.000000 -1.000000 0.00000
REMARK 290 SMTRY1 4 1.000000 0.000000 0.000000 35.67050
REMARK 290 SMTRY2 4 0.000000 -1.000000 0.000000 45.65900
REMARK 290 SMTRY3 4 0.000000 0.000000 -1.000000 0.00000
REMARK 290
REMARK 290 REMARK: NULL
REMARK 300
REMARK 300 BIOMOLECULE: 1
REMARK 300 SEE REMARK 350 FOR THE AUTHOR PROVIDED AND/OR PROGRAM
REMARK 300 GENERATED ASSEMBLY INFORMATION FOR THE STRUCTURE IN
REMARK 300 THIS ENTRY. THE REMARK MAY ALSO PROVIDE INFORMATION ON
REMARK 300 BURIED SURFACE AREA.
REMARK 350
REMARK 350 COORDINATES FOR A COMPLETE MULTIMER REPRESENTING THE KNOWN
REMARK 350 BIOLOGICALLY SIGNIFICANT OLIGOMERIZATION STATE OF THE
REMARK 350 MOLECULE CAN BE GENERATED BY APPLYING BIOMT TRANSFORMATIONS
REMARK 350 GIVEN BELOW. BOTH NON-CRYSTALLOGRAPHIC AND
REMARK 350 CRYSTALLOGRAPHIC OPERATIONS ARE GIVEN.
REMARK 350
REMARK 350 BIOMOLECULE: 1
REMARK 350 AUTHOR DETERMINED BIOLOGICAL UNIT: MONOMERIC
REMARK 350 SOFTWARE DETERMINED QUATERNARY STRUCTURE: MONOMERIC
REMARK 350 SOFTWARE USED: PISA
REMARK 350 APPLY THE FOLLOWING TO CHAINS: A
REMARK 350 BIOMT1 1 1.000000 0.000000 0.000000 0.00000
REMARK 350 BIOMT2 1 0.000000 1.000000 0.000000 0.00000
REMARK 350 BIOMT3 1 0.000000 0.000000 1.000000 0.00000
REMARK 465
REMARK 465 MISSING RESIDUES
REMARK 465 THE FOLLOWING RESIDUES WERE NOT LOCATED IN THE
REMARK 465 EXPERIMENT. (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN
REMARK 465 IDENTIFIER; SSSEQ=SEQUENCE NUMBER; I=INSERTION CODE.)
REMARK 465
REMARK 465 M RES C SSSEQI
REMARK 465 MET A -7
REMARK 465 ALA A -6
REMARK 465 HIS A -5
REMARK 465 HIS A -4
REMARK 465 HIS A -3
REMARK 465 HIS A -2
REMARK 465 HIS A -1
REMARK 465 HIS A 0
REMARK 465 MET A 1
REMARK 465 ALA A 2
REMARK 465 ALA A 3
REMARK 465 ALA A 4
REMARK 465 ALA A 5
REMARK 465 ALA A 6
REMARK 465 ALA A 7
REMARK 465 GLY A 8
REMARK 465 PRO A 9
REMARK 465 GLU A 10
REMARK 465 MET A 11
REMARK 465 VAL A 12
REMARK 465 ARG A 13
REMARK 465 GLY A 14
REMARK 465 GLN A 15
REMARK 465 GLY A 20
REMARK 465 PRO A 21
REMARK 465 ASN A 43
REMARK 465 LEU A 44
REMARK 465 ASN A 45
REMARK 465 LYS A 46
REMARK 465 VAL A 47
REMARK 465 LYS A 328
REMARK 465 PHE A 329
REMARK 465 ASP A 330
REMARK 465 MET A 331
REMARK 465 GLU A 332
REMARK 465 TYR A 356
REMARK 465 ARG A 357
REMARK 465 SER A 358
REMARK 500
REMARK 500 GEOMETRY AND STEREOCHEMISTRY
REMARK 500 SUBTOPIC: TORSION ANGLES
REMARK 500
REMARK 500 TORSION ANGLES OUTSIDE THE EXPECTED RAMACHANDRAN REGIONS:
REMARK 500 (M=MODEL NUMBER; RES=RESIDUE NAME; C=CHAIN IDENTIFIER;
REMARK 500 SSEQ=SEQUENCE NUMBER; I=INSERTION CODE).
REMARK 500
REMARK 500 STANDARD TABLE:
REMARK 500 FORMAT:(10X,I3,1X,A3,1X,A1,I4,A1,4X,F7.2,3X,F7.2)
REMARK 500
REMARK 500 EXPECTED VALUES: GJ KLEYWEGT AND TA JONES (1996). PHI/PSI-
REMARK 500 CHOLOGY: RAMACHANDRAN REVISITED. STRUCTURE 4, 1395 - 1400
REMARK 500
REMARK 500 M RES CSSEQI PSI PHI
REMARK 500 ASN A 25 74.22 55.19
REMARK 500 ASP A 147 41.45 -149.01
REMARK 500 ASP A 165 87.15 66.32
REMARK 500 ASP A 173 69.86 -153.70
REMARK 500 ASN A 199 12.98 -162.60
REMARK 500 LEU A 292 45.70 -96.67
REMARK 500
REMARK 500 REMARK: NULL
REMARK 800
REMARK 800 SITE
REMARK 800 SITE_IDENTIFIER: AC1
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: binding site for residue SO4 A 401
REMARK 800
REMARK 800 SITE_IDENTIFIER: AC2
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: binding site for residue SO4 A 402
REMARK 800
REMARK 800 SITE_IDENTIFIER: AC3
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: binding site for residue F8V A 403
DBREF 6CPW A 1 358 UNP P63086 MK01_RAT 1 358
SEQADV 6CPW MET A -7 UNP P63086 INITIATING METHIONINE
SEQADV 6CPW ALA A -6 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A -5 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A -4 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A -3 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A -2 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A -1 UNP P63086 EXPRESSION TAG
SEQADV 6CPW HIS A 0 UNP P63086 EXPRESSION TAG
SEQRES 1 A 366 MET ALA HIS HIS HIS HIS HIS HIS MET ALA ALA ALA ALA
SEQRES 2 A 366 ALA ALA GLY PRO GLU MET VAL ARG GLY GLN VAL PHE ASP
SEQRES 3 A 366 VAL GLY PRO ARG TYR THR ASN LEU SER TYR ILE GLY GLU
SEQRES 4 A 366 GLY ALA TYR GLY MET VAL CYS SER ALA TYR ASP ASN LEU
SEQRES 5 A 366 ASN LYS VAL ARG VAL ALA ILE LYS LYS ILE SER PRO PHE
SEQRES 6 A 366 GLU HIS GLN THR TYR CYS GLN ARG THR LEU ARG GLU ILE
SEQRES 7 A 366 LYS ILE LEU LEU ARG PHE ARG HIS GLU ASN ILE ILE GLY
SEQRES 8 A 366 ILE ASN ASP ILE ILE ARG ALA PRO THR ILE GLU GLN MET
SEQRES 9 A 366 LYS ASP VAL TYR ILE VAL GLN ASP LEU MET GLU THR ASP
SEQRES 10 A 366 LEU TYR LYS LEU LEU LYS THR GLN HIS LEU SER ASN ASP
SEQRES 11 A 366 HIS ILE CYS TYR PHE LEU TYR GLN ILE LEU ARG GLY LEU
SEQRES 12 A 366 LYS TYR ILE HIS SER ALA ASN VAL LEU HIS ARG ASP LEU
SEQRES 13 A 366 LYS PRO SER ASN LEU LEU LEU ASN THR THR CYS ASP LEU
SEQRES 14 A 366 LYS ILE CYS ASP PHE GLY LEU ALA ARG VAL ALA ASP PRO
SEQRES 15 A 366 ASP HIS ASP HIS THR GLY PHE LEU THR GLU TYR VAL ALA
SEQRES 16 A 366 THR ARG TRP TYR ARG ALA PRO GLU ILE MET LEU ASN SER
SEQRES 17 A 366 LYS GLY TYR THR LYS SER ILE ASP ILE TRP SER VAL GLY
SEQRES 18 A 366 CYS ILE LEU ALA GLU MET LEU SER ASN ARG PRO ILE PHE
SEQRES 19 A 366 PRO GLY LYS HIS TYR LEU ASP GLN LEU ASN HIS ILE LEU
SEQRES 20 A 366 GLY ILE LEU GLY SER PRO SER GLN GLU ASP LEU ASN CYS
SEQRES 21 A 366 ILE ILE ASN LEU LYS ALA ARG ASN TYR LEU LEU SER LEU
SEQRES 22 A 366 PRO HIS LYS ASN LYS VAL PRO TRP ASN ARG LEU PHE PRO
SEQRES 23 A 366 ASN ALA ASP SER LYS ALA LEU ASP LEU LEU ASP LYS MET
SEQRES 24 A 366 LEU THR PHE ASN PRO HIS LYS ARG ILE GLU VAL GLU GLN
SEQRES 25 A 366 ALA LEU ALA HIS PRO TYR LEU GLU GLN TYR TYR ASP PRO
SEQRES 26 A 366 SER ASP GLU PRO ILE ALA GLU ALA PRO PHE LYS PHE ASP
SEQRES 27 A 366 MET GLU LEU ASP ASP LEU PRO LYS GLU LYS LEU LYS GLU
SEQRES 28 A 366 LEU ILE PHE GLU GLU THR ALA ARG PHE GLN PRO GLY TYR
SEQRES 29 A 366 ARG SER
HET SO4 A 401 5
HET SO4 A 402 5
HET F8V A 403 83
HETNAM SO4 SULFATE ION
HETNAM F8V (3S)-N-[3-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL]-3-
HETNAM 2 F8V (METHYLSULFANYL)-1-(2-OXO-2-{4-[4-(PYRIMIDIN-2-YL)
HETNAM 3 F8V PHENYL]PIPERAZIN-1-YL}ETHYL)PYRROLIDINE-3-CARBOXAMIDE
FORMUL 2 SO4 2(O4 S 2-)
FORMUL 4 F8V C35 H35 F N8 O2 S
FORMUL 5 HOH *257(H2 O)
HELIX 1 AA1 HIS A 59 PHE A 76 1 18
HELIX 2 AA2 LEU A 110 GLN A 117 1 8
HELIX 3 AA3 SER A 120 ALA A 141 1 22
HELIX 4 AA4 LYS A 149 SER A 151 5 3
HELIX 5 AA5 ASP A 173 ASP A 177 5 5
HELIX 6 AA6 THR A 188 ALA A 193 5 6
HELIX 7 AA7 PRO A 194 ASN A 199 1 6
HELIX 8 AA8 LYS A 205 ASN A 222 1 18
HELIX 9 AA9 HIS A 230 GLY A 243 1 14
HELIX 10 AB1 SER A 246 CYS A 252 1 7
HELIX 11 AB2 ASN A 255 LEU A 265 1 11
HELIX 12 AB3 PRO A 272 PHE A 277 1 6
HELIX 13 AB4 ASP A 281 LEU A 292 1 12
HELIX 14 AB5 GLU A 301 ALA A 307 1 7
HELIX 15 AB6 HIS A 308 GLU A 312 5 5
HELIX 16 AB7 ASP A 316 GLU A 320 5 5
HELIX 17 AB8 PRO A 337 ALA A 350 1 14
HELIX 18 AB9 ARG A 351 GLN A 353 5 3
SHEET 1 AA1 5 THR A 24 GLY A 32 0
SHEET 2 AA1 5 GLY A 35 TYR A 41 -1 O TYR A 41 N THR A 24
SHEET 3 AA1 5 VAL A 49 ILE A 54 -1 O VAL A 49 N ALA A 40
SHEET 4 AA1 5 VAL A 99 ASP A 104 -1 O GLN A 103 N ALA A 50
SHEET 5 AA1 5 ASP A 86 ILE A 88 -1 N ASP A 86 O VAL A 102
SHEET 1 AA2 3 THR A 108 ASP A 109 0
SHEET 2 AA2 3 LEU A 153 LEU A 155 -1 O LEU A 155 N THR A 108
SHEET 3 AA2 3 LEU A 161 ILE A 163 -1 O LYS A 162 N LEU A 154
SHEET 1 AA3 2 VAL A 143 LEU A 144 0
SHEET 2 AA3 2 ARG A 170 VAL A 171 -1 O ARG A 170 N LEU A 144
SITE 1 AC1 8 TYR A 185 ARG A 189 ARG A 192 TYR A 231
SITE 2 AC1 8 HOH A 542 HOH A 607 HOH A 610 HOH A 642
SITE 1 AC2 7 ASN A 121 GLY A 180 LYS A 257 HOH A 507
SITE 2 AC2 7 HOH A 573 HOH A 597 HOH A 664
SITE 1 AC3 23 ILE A 29 ALA A 33 TYR A 34 ALA A 50
SITE 2 AC3 23 LYS A 52 ILE A 54 TYR A 62 THR A 66
SITE 3 AC3 23 GLU A 69 GLN A 103 ASP A 104 MET A 106
SITE 4 AC3 23 GLU A 107 THR A 108 LYS A 112 SER A 151
SITE 5 AC3 23 ASN A 152 LEU A 154 CYS A 164 ASP A 165
SITE 6 AC3 23 GLY A 167 HOH A 509 HOH A 702
CRYST1 71.341 91.318 63.289 90.00 90.00 90.00 P 21 21 2 4
ORIGX1 1.000000 0.000000 0.000000 0.00000
ORIGX2 0.000000 1.000000 0.000000 0.00000
ORIGX3 0.000000 0.000000 1.000000 0.00000
SCALE1 0.014017 0.000000 0.000000 0.00000
SCALE2 0.000000 0.010951 0.000000 0.00000
SCALE3 0.000000 0.000000 0.015801 0.00000
(ATOM LINES ARE NOT SHOWN.)
END
