HEADER TRANSFERASE/TRANSFERASE INHIBITOR 06-MAY-18 6DCG
TITLE DISCOVERY OF MK-8353: AN ORALLY BIOAVAILABLE DUAL MECHANISM ERK
TITLE 2 INHIBITOR 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;
SOURCE 7 EXPRESSION_SYSTEM_TAXID: 562
KEYWDS KINASE INHIBITOR, KINASE SELECTIVITY, TRANSFERASE, SERINE/ THREONINE-
KEYWDS 2 PROTEIN KINASE, MAP KINASE, TRANSFERASE-TRANSFERASE INHIBITOR
KEYWDS 3 COMPLEX
EXPDTA X-RAY DIFFRACTION
AUTHOR S.B.BOGA,Y.DENG,L.ZHU,Y.NAN,A.COOPER,G.W.SHIPPS JR.,R.DOLL,N.SHIH,
AUTHOR 2 H.ZHU,R.SUN,T.WANG,S.PALIWAL,H.TSUI,X.GAO,X.YAO,J.DESAI,J.WANG,
AUTHOR 3 A.B.ALHASSAN,J.KELLY,M.PATEL,K.MUPPALLA,S.GUDIPATI,L.ZHANG,
AUTHOR 4 A.BUEVICH,D.HESK,D.CARR,P.DAYANANTH,H.MEI,K.COX,B.SHERBORNE,
AUTHOR 5 A.W.HRUZA,L.XIAO,W.JIN,B.LONG,G.LIU,S.A.TAYLOR,P.KIRSCHMEIER,
AUTHOR 6 W.T.WINDSOR,R.BISHOP,A.A.SAMATAR
REVDAT 1 08-AUG-18 6DCG 0
JRNL AUTH S.B.BOGA,Y.DENG,L.ZHU,Y.NAN,A.B.COOPER,G.W.SHIPPS JR.,
JRNL AUTH 2 R.DOLL,N.Y.SHIH,H.ZHU,R.SUN,T.WANG,S.PALIWAL,H.C.TSUI,X.GAO,
JRNL AUTH 3 X.YAO,J.DESAI,J.WANG,A.B.ALHASSAN,J.KELLY,M.PATEL,
JRNL AUTH 4 K.MUPPALLA,S.GUDIPATI,L.K.ZHANG,A.BUEVICH,D.HESK,D.CARR,
JRNL AUTH 5 P.DAYANANTH,S.BLACK,H.MEI,K.COX,B.SHERBORNE,A.W.HRUZA,
JRNL AUTH 6 L.XIAO,W.JIN,B.LONG,G.LIU,S.A.TAYLOR,P.KIRSCHMEIER,
JRNL AUTH 7 W.T.WINDSOR,R.BISHOP,A.A.SAMATAR
JRNL TITL MK-8353: DISCOVERY OF AN ORALLY BIOAVAILABLE DUAL MECHANISM
JRNL TITL 2 ERK INHIBITOR FOR ONCOLOGY.
JRNL REF ACS MED CHEM LETT V. 9 761 2018
JRNL REFN ISSN 1948-5875
JRNL PMID 30034615
JRNL DOI 10.1021/ACSMEDCHEMLETT.8B00220
REMARK 2
REMARK 2 RESOLUTION. 1.45 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) : 1.45
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 29.79
REMARK 3 DATA CUTOFF (SIGMA(F)) : 0.000
REMARK 3 COMPLETENESS FOR RANGE (%) : 97.1
REMARK 3 NUMBER OF REFLECTIONS : 70111
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) : 0.178
REMARK 3 R VALUE (WORKING SET) : 0.177
REMARK 3 FREE R VALUE : 0.199
REMARK 3 FREE R VALUE TEST SET SIZE (%) : 5.000
REMARK 3 FREE R VALUE TEST SET COUNT : 3509
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 : 20
REMARK 3 BIN RESOLUTION RANGE HIGH (ANGSTROMS) : 1.45
REMARK 3 BIN RESOLUTION RANGE LOW (ANGSTROMS) : 1.49
REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) : 95.27
REMARK 3 REFLECTIONS IN BIN (WORKING + TEST SET) : 5012
REMARK 3 BIN R VALUE (WORKING + TEST SET) : 0.2150
REMARK 3 REFLECTIONS IN BIN (WORKING SET) : 4739
REMARK 3 BIN R VALUE (WORKING SET) : 0.2130
REMARK 3 BIN FREE R VALUE : 0.2490
REMARK 3 BIN FREE R VALUE TEST SET SIZE (%) : 5.45
REMARK 3 BIN FREE R VALUE TEST SET COUNT : 273
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 : 2667
REMARK 3 NUCLEIC ACID ATOMS : 0
REMARK 3 HETEROGEN ATOMS : 60
REMARK 3 SOLVENT ATOMS : 249
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2) : 18.88
REMARK 3 MEAN B VALUE (OVERALL, A**2) : 25.46
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2) : -0.81490
REMARK 3 B22 (A**2) : -0.29670
REMARK 3 B33 (A**2) : 1.11150
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) : 0.170
REMARK 3 DPI (BLOW EQ-10) BASED ON R VALUE (A) : 0.061
REMARK 3 DPI (BLOW EQ-9) BASED ON FREE R VALUE (A) : 0.061
REMARK 3 DPI (CRUICKSHANK) BASED ON R VALUE (A) : 0.065
REMARK 3 DPI (CRUICKSHANK) BASED ON FREE R VALUE (A) : 0.060
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 : 0.954
REMARK 3 CORRELATION COEFFICIENT FO-FC FREE : 0.950
REMARK 3
REMARK 3 NUMBER OF GEOMETRIC FUNCTION TERMS DEFINED : 15
REMARK 3 TERM COUNT WEIGHT FUNCTION.
REMARK 3 BOND LENGTHS : 5565 ; 2.000 ; HARMONIC
REMARK 3 BOND ANGLES : 10063 ; 2.000 ; HARMONIC
REMARK 3 TORSION ANGLES : 1233 ; 2.000 ; SINUSOIDAL
REMARK 3 TRIGONAL CARBON PLANES : 68 ; 2.000 ; HARMONIC
REMARK 3 GENERAL PLANES : 847 ; 5.000 ; HARMONIC
REMARK 3 ISOTROPIC THERMAL FACTORS : 5565 ; 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 : 360 ; 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 : 6348 ; 4.000 ; SEMIHARMONIC
REMARK 3
REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES.
REMARK 3 BOND LENGTHS (A) : 0.010
REMARK 3 BOND ANGLES (DEGREES) : 1.06
REMARK 3 PEPTIDE OMEGA TORSION ANGLES (DEGREES) : 3.92
REMARK 3 OTHER TORSION ANGLES (DEGREES) : 14.75
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): 52.0270 19.0191 19.8772
REMARK 3 T TENSOR
REMARK 3 T11: -0.0492 T22: -0.0608
REMARK 3 T33: -0.0598 T12: 0.0154
REMARK 3 T13: -0.0113 T23: -0.0024
REMARK 3 L TENSOR
REMARK 3 L11: 1.0783 L22: 0.5807
REMARK 3 L33: 0.8631 L12: -0.4559
REMARK 3 L13: -0.5731 L23: 0.1968
REMARK 3 S TENSOR
REMARK 3 S11: 0.0538 S12: 0.1637 S13: -0.0866
REMARK 3 S21: -0.0661 S22: -0.0848 S23: 0.0871
REMARK 3 S31: -0.0398 S32: -0.1087 S33: 0.0310
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS: NULL
REMARK 4
REMARK 4 6DCG COMPLIES WITH FORMAT V. 3.30, 13-JUL-11
REMARK 100
REMARK 100 THIS ENTRY HAS BEEN PROCESSED BY RCSB ON 09-MAY-18.
REMARK 100 THE DEPOSITION ID IS D_1000234372.
REMARK 200
REMARK 200 EXPERIMENTAL DETAILS
REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION
REMARK 200 DATE OF DATA COLLECTION : 06-MAY-08
REMARK 200 TEMPERATURE (KELVIN) : 100
REMARK 200 PH : 6.4
REMARK 200 NUMBER OF CRYSTALS USED : 1
REMARK 200
REMARK 200 SYNCHROTRON (Y/N) : Y
REMARK 200 RADIATION SOURCE : CHESS
REMARK 200 BEAMLINE : A1
REMARK 200 X-RAY GENERATOR MODEL : NULL
REMARK 200 MONOCHROMATIC OR LAUE (M/L) : M
REMARK 200 WAVELENGTH OR RANGE (A) : 0.97770
REMARK 200 MONOCHROMATOR : NULL
REMARK 200 OPTICS : NULL
REMARK 200
REMARK 200 DETECTOR TYPE : CCD
REMARK 200 DETECTOR MANUFACTURER : ADSC QUANTUM 210
REMARK 200 INTENSITY-INTEGRATION SOFTWARE : DENZO
REMARK 200 DATA SCALING SOFTWARE : HKL-2000
REMARK 200
REMARK 200 NUMBER OF UNIQUE REFLECTIONS : 70144
REMARK 200 RESOLUTION RANGE HIGH (A) : 1.450
REMARK 200 RESOLUTION RANGE LOW (A) : 30.000
REMARK 200 REJECTION CRITERIA (SIGMA(I)) : NULL
REMARK 200
REMARK 200 OVERALL.
REMARK 200 COMPLETENESS FOR RANGE (%) : 97.1
REMARK 200 DATA REDUNDANCY : 5.200
REMARK 200 R MERGE (I) : 0.04800
REMARK 200 R SYM (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : 27.1000
REMARK 200
REMARK 200 IN THE HIGHEST RESOLUTION SHELL.
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.45
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.48
REMARK 200 COMPLETENESS FOR SHELL (%) : 94.7
REMARK 200 DATA REDUNDANCY IN SHELL : 3.60
REMARK 200 R MERGE FOR SHELL (I) : 0.56400
REMARK 200 R SYM FOR SHELL (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR SHELL : 2.100
REMARK 200
REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH
REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: MOLECULAR REPLACEMENT
REMARK 200 SOFTWARE USED: MOLREP
REMARK 200 STARTING MODEL: 1ERK
REMARK 200
REMARK 200 REMARK: NULL
REMARK 280
REMARK 280 CRYSTAL
REMARK 280 SOLVENT CONTENT, VS (%): 48.22
REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.38
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 35.00900
REMARK 290 SMTRY2 3 0.000000 1.000000 0.000000 45.58650
REMARK 290 SMTRY3 3 0.000000 0.000000 -1.000000 0.00000
REMARK 290 SMTRY1 4 1.000000 0.000000 0.000000 35.00900
REMARK 290 SMTRY2 4 0.000000 -1.000000 0.000000 45.58650
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 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 LEU A 333
REMARK 465 ASP A 334
REMARK 465 ASP A 335
REMARK 465 GLY A 355
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 ILE A 29 -60.70 -105.87
REMARK 500 ASP A 147 42.22 -151.13
REMARK 500 ASP A 165 87.53 70.91
REMARK 500 ASP A 165 87.53 60.63
REMARK 500 ASP A 173 69.05 -152.20
REMARK 500 ASN A 199 10.61 -162.58
REMARK 500 ILE A 254 -62.11 74.50
REMARK 500 LEU A 292 43.34 -94.13
REMARK 500 LEU A 292 43.34 -99.03
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 G67 A 403
DBREF 6DCG A 1 358 UNP P63086 MK01_RAT 1 358
SEQADV 6DCG MET A -7 UNP P63086 INITIATING METHIONINE
SEQADV 6DCG ALA A -6 UNP P63086 EXPRESSION TAG
SEQADV 6DCG HIS A -5 UNP P63086 EXPRESSION TAG
SEQADV 6DCG HIS A -4 UNP P63086 EXPRESSION TAG
SEQADV 6DCG HIS A -3 UNP P63086 EXPRESSION TAG
SEQADV 6DCG HIS A -2 UNP P63086 EXPRESSION TAG
SEQADV 6DCG HIS A -1 UNP P63086 EXPRESSION TAG
SEQADV 6DCG 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 G67 A 403 92
HETNAM SO4 SULFATE ION
HETNAM G67 (3S)-3-(METHYLSULFANYL)-1-(2-{4-[4-(1-METHYL-1H-1,2,4-
HETNAM 2 G67 TRIAZOL-3-YL)PHENYL]-3,6-DIHYDROPYRIDIN-1(2H)-YL}-2-
HETNAM 3 G67 OXOETHYL)-N-(3-{6-[(PROPAN-2-YL)OXY]PYRIDIN-3-YL}-1H-
HETNAM 4 G67 INDAZOL-5-YL)PYRROLIDINE-3-CARBOXAMIDE
FORMUL 2 SO4 2(O4 S 2-)
FORMUL 4 G67 C37 H41 N9 O3 S
FORMUL 5 HOH *249(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 ARG A 192 5 5
HELIX 7 AA7 ALA A 193 MET A 197 5 5
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 VAL A 99 N ILE A 54
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
CISPEP 1 GLY A 20 PRO A 21 0 1.50
SITE 1 AC1 8 TYR A 185 ARG A 189 ARG A 192 TYR A 231
SITE 2 AC1 8 HOH A 569 HOH A 574 HOH A 587 HOH A 642
SITE 1 AC2 11 ASN A 121 ASP A 122 GLY A 180 LYS A 257
SITE 2 AC2 11 HOH A 556 HOH A 568 HOH A 631 HOH A 634
SITE 3 AC2 11 HOH A 646 HOH A 665 HOH A 673
SITE 1 AC3 21 ALA A 33 TYR A 34 ALA A 50 LYS A 52
SITE 2 AC3 21 TYR A 62 THR A 66 GLU A 69 GLN A 103
SITE 3 AC3 21 ASP A 104 LEU A 105 MET A 106 GLU A 107
SITE 4 AC3 21 LYS A 112 SER A 151 ASN A 152 LEU A 154
SITE 5 AC3 21 CYS A 164 ASP A 165 GLY A 167 HOH A 508
SITE 6 AC3 21 HOH A 592
CRYST1 70.018 91.173 63.051 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 0.014282 0.000000 0.000000 0.00000
SCALE2 0.000000 0.010968 0.000000 0.00000
SCALE3 0.000000 0.000000 0.015860 0.00000
(ATOM LINES ARE NOT SHOWN.)
END
