HEADER PROTEIN BINDING/INHIBITOR 12-NOV-12 4HXL
TITLE BRD4 BROMODOMAIN 1 COMPLEX WITH 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-
TITLE 2 1,3-THIAZOL-4-YL)-5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE
TITLE 3 INHIBITOR
COMPND MOL_ID: 1;
COMPND 2 MOLECULE: BROMODOMAIN-CONTAINING PROTEIN 4;
COMPND 3 CHAIN: A;
COMPND 4 SYNONYM: PROTEIN HUNK1;
COMPND 5 ENGINEERED: YES
SOURCE MOL_ID: 1;
SOURCE 2 ORGANISM_SCIENTIFIC: HOMO SAPIENS;
SOURCE 3 ORGANISM_COMMON: HUMAN;
SOURCE 4 ORGANISM_TAXID: 9606;
SOURCE 5 GENE: BRD4, HUNK1;
SOURCE 6 EXPRESSION_SYSTEM: ESCHERICHIA COLI;
SOURCE 7 EXPRESSION_SYSTEM_TAXID: 562;
SOURCE 8 EXPRESSION_SYSTEM_STRAIN: BL21(DE3)CODON PLUS;
SOURCE 9 EXPRESSION_SYSTEM_VECTOR_TYPE: PLASMID;
SOURCE 10 EXPRESSION_SYSTEM_PLASMID: PET28A
KEYWDS BRD4, BROMODOMAIN, FOUR ALPHA HELICES, PROTEIN BINDING-INHIBITOR
KEYWDS 2 COMPLEX
EXPDTA X-RAY DIFFRACTION
AUTHOR T.T.CHEN,D.Y.CAO,W.Y.CHEN,B.XIONG,J.K.SHEN,Y.C.XU
REVDAT 4 28-FEB-24 4HXL 1 REMARK SEQADV
REVDAT 3 19-JUN-13 4HXL 1 JRNL
REVDAT 2 10-APR-13 4HXL 1 AUTHOR
REVDAT 1 03-APR-13 4HXL 0
JRNL AUTH L.ZHAO,D.CAO,T.CHEN,Y.WANG,Z.MIAO,Y.XU,W.CHEN,X.WANG,Y.LI,
JRNL AUTH 2 Z.DU,B.XIONG,J.LI,C.XU,N.ZHANG,J.HE,J.SHEN
JRNL TITL FRAGMENT-BASED DRUG DISCOVERY OF 2-THIAZOLIDINONES AS
JRNL TITL 2 INHIBITORS OF THE HISTONE READER BRD4 BROMODOMAIN.
JRNL REF J.MED.CHEM. V. 56 3833 2013
JRNL REFN ISSN 0022-2623
JRNL PMID 23530754
JRNL DOI 10.1021/JM301793A
REMARK 2
REMARK 2 RESOLUTION. 1.52 ANGSTROMS.
REMARK 3
REMARK 3 REFINEMENT.
REMARK 3 PROGRAM : PHENIX 1.8_1069
REMARK 3 AUTHORS : PAUL ADAMS,PAVEL AFONINE,VINCENT CHEN,IAN
REMARK 3 : DAVIS,KRESHNA GOPAL,RALF GROSSE-KUNSTLEVE,
REMARK 3 : LI-WEI HUNG,ROBERT IMMORMINO,TOM IOERGER,
REMARK 3 : AIRLIE MCCOY,ERIK MCKEE,NIGEL MORIARTY,
REMARK 3 : REETAL PAI,RANDY READ,JANE RICHARDSON,
REMARK 3 : DAVID RICHARDSON,TOD ROMO,JIM SACCHETTINI,
REMARK 3 : NICHOLAS SAUTER,JACOB SMITH,LAURENT
REMARK 3 : STORONI,TOM TERWILLIGER,PETER ZWART
REMARK 3
REMARK 3 REFINEMENT TARGET : MLHL
REMARK 3
REMARK 3 DATA USED IN REFINEMENT.
REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS) : 1.52
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 30.28
REMARK 3 MIN(FOBS/SIGMA_FOBS) : 2.010
REMARK 3 COMPLETENESS FOR RANGE (%) : 99.1
REMARK 3 NUMBER OF REFLECTIONS : 18944
REMARK 3
REMARK 3 FIT TO DATA USED IN REFINEMENT.
REMARK 3 R VALUE (WORKING + TEST SET) : 0.171
REMARK 3 R VALUE (WORKING SET) : 0.170
REMARK 3 FREE R VALUE : 0.191
REMARK 3 FREE R VALUE TEST SET SIZE (%) : 3.000
REMARK 3 FREE R VALUE TEST SET COUNT : 568
REMARK 3
REMARK 3 FIT TO DATA USED IN REFINEMENT (IN BINS).
REMARK 3 BIN RESOLUTION RANGE COMPL. NWORK NFREE RWORK RFREE
REMARK 3 1 30.2855 - 2.4126 0.98 4734 147 0.1739 0.1860
REMARK 3 2 2.4126 - 1.9151 1.00 4600 142 0.1704 0.1924
REMARK 3 3 1.9151 - 1.6730 0.99 4527 140 0.1639 0.2091
REMARK 3 4 1.6730 - 1.5201 0.99 4515 139 0.1624 0.1930
REMARK 3
REMARK 3 BULK SOLVENT MODELLING.
REMARK 3 METHOD USED : FLAT BULK SOLVENT MODEL
REMARK 3 SOLVENT RADIUS : 1.11
REMARK 3 SHRINKAGE RADIUS : 0.90
REMARK 3 K_SOL : NULL
REMARK 3 B_SOL : NULL
REMARK 3
REMARK 3 ERROR ESTIMATES.
REMARK 3 COORDINATE ERROR (MAXIMUM-LIKELIHOOD BASED) : 0.080
REMARK 3 PHASE ERROR (DEGREES, MAXIMUM-LIKELIHOOD BASED) : 18.980
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2) : 18.99
REMARK 3 MEAN B VALUE (OVERALL, A**2) : 17.61
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2) : NULL
REMARK 3 B22 (A**2) : NULL
REMARK 3 B33 (A**2) : NULL
REMARK 3 B12 (A**2) : NULL
REMARK 3 B13 (A**2) : NULL
REMARK 3 B23 (A**2) : NULL
REMARK 3
REMARK 3 TWINNING INFORMATION.
REMARK 3 FRACTION: NULL
REMARK 3 OPERATOR: NULL
REMARK 3
REMARK 3 DEVIATIONS FROM IDEAL VALUES.
REMARK 3 RMSD COUNT
REMARK 3 BOND : 0.006 1107
REMARK 3 ANGLE : 1.144 1508
REMARK 3 CHIRALITY : 0.074 157
REMARK 3 PLANARITY : 0.005 192
REMARK 3 DIHEDRAL : 15.561 434
REMARK 3
REMARK 3 TLS DETAILS
REMARK 3 NUMBER OF TLS GROUPS : NULL
REMARK 3
REMARK 3 NCS DETAILS
REMARK 3 NUMBER OF NCS GROUPS : NULL
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS: NULL
REMARK 4
REMARK 4 4HXL COMPLIES WITH FORMAT V. 3.30, 13-JUL-11
REMARK 100
REMARK 100 THIS ENTRY HAS BEEN PROCESSED BY RCSB ON 15-NOV-12.
REMARK 100 THE DEPOSITION ID IS D_1000076046.
REMARK 200
REMARK 200 EXPERIMENTAL DETAILS
REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION
REMARK 200 DATE OF DATA COLLECTION : 21-OCT-12
REMARK 200 TEMPERATURE (KELVIN) : 100
REMARK 200 PH : NULL
REMARK 200 NUMBER OF CRYSTALS USED : 1
REMARK 200
REMARK 200 SYNCHROTRON (Y/N) : Y
REMARK 200 RADIATION SOURCE : SSRF
REMARK 200 BEAMLINE : BL17U
REMARK 200 X-RAY GENERATOR MODEL : NULL
REMARK 200 MONOCHROMATIC OR LAUE (M/L) : M
REMARK 200 WAVELENGTH OR RANGE (A) : 0.979
REMARK 200 MONOCHROMATOR : NULL
REMARK 200 OPTICS : NULL
REMARK 200
REMARK 200 DETECTOR TYPE : CCD
REMARK 200 DETECTOR MANUFACTURER : ADSC QUANTUM 315R
REMARK 200 INTENSITY-INTEGRATION SOFTWARE : XDS
REMARK 200 DATA SCALING SOFTWARE : XSCALE
REMARK 200
REMARK 200 NUMBER OF UNIQUE REFLECTIONS : NULL
REMARK 200 RESOLUTION RANGE HIGH (A) : 1.520
REMARK 200 RESOLUTION RANGE LOW (A) : 30.279
REMARK 200 REJECTION CRITERIA (SIGMA(I)) : -3.000
REMARK 200
REMARK 200 OVERALL.
REMARK 200 COMPLETENESS FOR RANGE (%) : 99.1
REMARK 200 DATA REDUNDANCY : NULL
REMARK 200 R MERGE (I) : 0.04000
REMARK 200 R SYM (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : 21.4900
REMARK 200
REMARK 200 IN THE HIGHEST RESOLUTION SHELL.
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.52
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.56
REMARK 200 COMPLETENESS FOR SHELL (%) : 99.4
REMARK 200 DATA REDUNDANCY IN SHELL : NULL
REMARK 200 R MERGE FOR SHELL (I) : 0.13200
REMARK 200 R SYM FOR SHELL (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR SHELL : 9.420
REMARK 200
REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH
REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: MOLECULAR REPLACEMENT
REMARK 200 SOFTWARE USED: PHASER 2.1.4
REMARK 200 STARTING MODEL: NULL
REMARK 200
REMARK 200 REMARK: NULL
REMARK 280
REMARK 280 CRYSTAL
REMARK 280 SOLVENT CONTENT, VS (%): 38.74
REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.01
REMARK 280
REMARK 280 CRYSTALLIZATION CONDITIONS: 3.6M NA FORMATE, 10% GLYCEROL, VAPOR
REMARK 280 DIFFUSION, HANGING DROP, TEMPERATURE 293K
REMARK 290
REMARK 290 CRYSTALLOGRAPHIC SYMMETRY
REMARK 290 SYMMETRY OPERATORS FOR SPACE GROUP: P 21 21 21
REMARK 290
REMARK 290 SYMOP SYMMETRY
REMARK 290 NNNMMM OPERATOR
REMARK 290 1555 X,Y,Z
REMARK 290 2555 -X+1/2,-Y,Z+1/2
REMARK 290 3555 -X,Y+1/2,-Z+1/2
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 16.05000
REMARK 290 SMTRY2 2 0.000000 -1.000000 0.000000 0.00000
REMARK 290 SMTRY3 2 0.000000 0.000000 1.000000 39.52500
REMARK 290 SMTRY1 3 -1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 3 0.000000 1.000000 0.000000 23.55500
REMARK 290 SMTRY3 3 0.000000 0.000000 -1.000000 39.52500
REMARK 290 SMTRY1 4 1.000000 0.000000 0.000000 16.05000
REMARK 290 SMTRY2 4 0.000000 -1.000000 0.000000 23.55500
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 470
REMARK 470 MISSING ATOM
REMARK 470 THE FOLLOWING RESIDUES HAVE MISSING ATOMS (M=MODEL NUMBER;
REMARK 470 RES=RESIDUE NAME; C=CHAIN IDENTIFIER; SSEQ=SEQUENCE NUMBER;
REMARK 470 I=INSERTION CODE):
REMARK 470 M RES CSSEQI ATOMS
REMARK 470 GLU A 167 CG CD OE1 OE2
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 52 107.29 -161.12
REMARK 500 ASN A 140 -147.34 -112.56
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 1A9 A 201
REMARK 900
REMARK 900 RELATED ENTRIES
REMARK 900 RELATED ID: 4HXK RELATED DB: PDB
REMARK 900 RELATED ID: 4HXM RELATED DB: PDB
REMARK 900 RELATED ID: 4HXN RELATED DB: PDB
REMARK 900 RELATED ID: 4HXO RELATED DB: PDB
REMARK 900 RELATED ID: 4HXP RELATED DB: PDB
REMARK 900 RELATED ID: 4HXR RELATED DB: PDB
REMARK 900 RELATED ID: 4HXS RELATED DB: PDB
DBREF 4HXL A 44 167 UNP O60885 BRD4_HUMAN 44 167
SEQADV 4HXL MET A 43 UNP O60885 EXPRESSION TAG
SEQRES 1 A 125 MET ASN PRO PRO PRO PRO GLU THR SER ASN PRO ASN LYS
SEQRES 2 A 125 PRO LYS ARG GLN THR ASN GLN LEU GLN TYR LEU LEU ARG
SEQRES 3 A 125 VAL VAL LEU LYS THR LEU TRP LYS HIS GLN PHE ALA TRP
SEQRES 4 A 125 PRO PHE GLN GLN PRO VAL ASP ALA VAL LYS LEU ASN LEU
SEQRES 5 A 125 PRO ASP TYR TYR LYS ILE ILE LYS THR PRO MET ASP MET
SEQRES 6 A 125 GLY THR ILE LYS LYS ARG LEU GLU ASN ASN TYR TYR TRP
SEQRES 7 A 125 ASN ALA GLN GLU CYS ILE GLN ASP PHE ASN THR MET PHE
SEQRES 8 A 125 THR ASN CYS TYR ILE TYR ASN LYS PRO GLY ASP ASP ILE
SEQRES 9 A 125 VAL LEU MET ALA GLU ALA LEU GLU LYS LEU PHE LEU GLN
SEQRES 10 A 125 LYS ILE ASN GLU LEU PRO THR GLU
HET 1A9 A 201 32
HETNAM 1A9 3-CYCLOHEXYL-N-{3-(2-OXO-2,3-DIHYDRO-1,3-THIAZOL-4-YL)-
HETNAM 2 1A9 5-[(THIOPHEN-2-YLSULFONYL)AMINO]PHENYL}PROPANAMIDE
FORMUL 2 1A9 C22 H25 N3 O4 S3
FORMUL 3 HOH *152(H2 O)
HELIX 1 1 THR A 60 VAL A 69 1 10
HELIX 2 2 VAL A 69 TRP A 75 1 7
HELIX 3 3 ALA A 80 GLN A 84 5 5
HELIX 4 4 ASP A 96 ILE A 101 1 6
HELIX 5 5 ASP A 106 ASN A 116 1 11
HELIX 6 6 ASN A 121 ASN A 140 1 20
HELIX 7 7 ASP A 144 ASN A 162 1 19
SITE 1 AC1 15 TRP A 81 PRO A 82 GLN A 85 LEU A 92
SITE 2 AC1 15 ASN A 93 ASP A 96 LYS A 99 ILE A 100
SITE 3 AC1 15 ASN A 140 ILE A 146 HOH A 307 HOH A 325
SITE 4 AC1 15 HOH A 364 HOH A 374 HOH A 380
CRYST1 32.100 47.110 79.050 90.00 90.00 90.00 P 21 21 21 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 0.031153 0.000000 0.000000 0.00000
SCALE2 0.000000 0.021227 0.000000 0.00000
SCALE3 0.000000 0.000000 0.012650 0.00000
(ATOM LINES ARE NOT SHOWN.)
END