HEADER PROTEIN BINDING/INHIBITOR 12-NOV-12 4HXK
TITLE BRD4 BROMODOMAIN 1 COMPLEX WITH 6,7-DIHYDROTHIENO[3,2-C]PYRIDIN-5(4H)-
TITLE 2 YL(1H-IMIDAZOL-1-YL)METHANONE 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 5 28-FEB-24 4HXK 1 REMARK SEQADV
REVDAT 4 17-JUL-19 4HXK 1 REMARK
REVDAT 3 19-JUN-13 4HXK 1 JRNL
REVDAT 2 10-APR-13 4HXK 1 AUTHOR
REVDAT 1 03-APR-13 4HXK 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. 1.61 ANGSTROMS.
REMARK 3
REMARK 3 REFINEMENT.
REMARK 3 PROGRAM : REFMAC 5.6.0117
REMARK 3 AUTHORS : MURSHUDOV,SKUBAK,LEBEDEV,PANNU,STEINER,
REMARK 3 : NICHOLLS,WINN,LONG,VAGIN
REMARK 3
REMARK 3 REFINEMENT TARGET : MAXIMUM LIKELIHOOD
REMARK 3
REMARK 3 DATA USED IN REFINEMENT.
REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS) : 1.61
REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 30.27
REMARK 3 DATA CUTOFF (SIGMA(F)) : NULL
REMARK 3 COMPLETENESS FOR RANGE (%) : 99.0
REMARK 3 NUMBER OF REFLECTIONS : 15588
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) : 0.180
REMARK 3 R VALUE (WORKING SET) : 0.180
REMARK 3 FREE R VALUE : 0.203
REMARK 3 FREE R VALUE TEST SET SIZE (%) : 3.000
REMARK 3 FREE R VALUE TEST SET COUNT : 483
REMARK 3
REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN.
REMARK 3 TOTAL NUMBER OF BINS USED : 20
REMARK 3 BIN RESOLUTION RANGE HIGH (A) : 1.61
REMARK 3 BIN RESOLUTION RANGE LOW (A) : 1.65
REMARK 3 REFLECTION IN BIN (WORKING SET) : 1021
REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) : 99.72
REMARK 3 BIN R VALUE (WORKING SET) : 0.1890
REMARK 3 BIN FREE R VALUE SET COUNT : 31
REMARK 3 BIN FREE R VALUE : 0.2570
REMARK 3
REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT.
REMARK 3 PROTEIN ATOMS : 1042
REMARK 3 NUCLEIC ACID ATOMS : 0
REMARK 3 HETEROGEN ATOMS : 16
REMARK 3 SOLVENT ATOMS : 98
REMARK 3
REMARK 3 B VALUES.
REMARK 3 FROM WILSON PLOT (A**2) : NULL
REMARK 3 MEAN B VALUE (OVERALL, A**2) : 22.84
REMARK 3 OVERALL ANISOTROPIC B VALUE.
REMARK 3 B11 (A**2) : 2.65000
REMARK 3 B22 (A**2) : -1.27000
REMARK 3 B33 (A**2) : -1.38000
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 OVERALL COORDINATE ERROR.
REMARK 3 ESU BASED ON R VALUE (A): 0.096
REMARK 3 ESU BASED ON FREE R VALUE (A): 0.090
REMARK 3 ESU BASED ON MAXIMUM LIKELIHOOD (A): 0.062
REMARK 3 ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2): 1.770
REMARK 3
REMARK 3 CORRELATION COEFFICIENTS.
REMARK 3 CORRELATION COEFFICIENT FO-FC : 0.964
REMARK 3 CORRELATION COEFFICIENT FO-FC FREE : 0.960
REMARK 3
REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES COUNT RMS WEIGHT
REMARK 3 BOND LENGTHS REFINED ATOMS (A): 1095 ; 0.025 ; 0.020
REMARK 3 BOND LENGTHS OTHERS (A): NULL ; NULL ; NULL
REMARK 3 BOND ANGLES REFINED ATOMS (DEGREES): 1493 ; 1.993 ; 1.986
REMARK 3 BOND ANGLES OTHERS (DEGREES): NULL ; NULL ; NULL
REMARK 3 TORSION ANGLES, PERIOD 1 (DEGREES): 126 ; 4.967 ; 5.000
REMARK 3 TORSION ANGLES, PERIOD 2 (DEGREES): 52 ;36.813 ;25.769
REMARK 3 TORSION ANGLES, PERIOD 3 (DEGREES): 193 ;12.596 ;15.000
REMARK 3 TORSION ANGLES, PERIOD 4 (DEGREES): 3 ;22.849 ;15.000
REMARK 3 CHIRAL-CENTER RESTRAINTS (A**3): 158 ; 0.146 ; 0.200
REMARK 3 GENERAL PLANES REFINED ATOMS (A): 839 ; 0.013 ; 0.022
REMARK 3 GENERAL PLANES OTHERS (A): NULL ; NULL ; NULL
REMARK 3 NON-BONDED CONTACTS REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 NON-BONDED CONTACTS OTHERS (A): NULL ; NULL ; NULL
REMARK 3 NON-BONDED TORSION REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 NON-BONDED TORSION OTHERS (A): NULL ; NULL ; NULL
REMARK 3 H-BOND (X...Y) REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 H-BOND (X...Y) OTHERS (A): NULL ; NULL ; NULL
REMARK 3 POTENTIAL METAL-ION REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 POTENTIAL METAL-ION OTHERS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY VDW REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY VDW OTHERS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY H-BOND REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY H-BOND OTHERS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY METAL-ION REFINED ATOMS (A): NULL ; NULL ; NULL
REMARK 3 SYMMETRY METAL-ION OTHERS (A): NULL ; NULL ; NULL
REMARK 3
REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. COUNT RMS WEIGHT
REMARK 3 MAIN-CHAIN BOND REFINED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 MAIN-CHAIN BOND OTHER ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 MAIN-CHAIN ANGLE REFINED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 MAIN-CHAIN ANGLE OTHER ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 SIDE-CHAIN BOND REFINED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 SIDE-CHAIN BOND OTHER ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 SIDE-CHAIN ANGLE REFINED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 SIDE-CHAIN ANGLE OTHER ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 LONG RANGE B REFINED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 LONG RANGE B OTHER ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3
REMARK 3 ANISOTROPIC THERMAL FACTOR RESTRAINTS. COUNT RMS WEIGHT
REMARK 3 RIGID-BOND RESTRAINTS (A**2): NULL ; NULL ; NULL
REMARK 3 SPHERICITY; FREE ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3 SPHERICITY; BONDED ATOMS (A**2): NULL ; NULL ; NULL
REMARK 3
REMARK 3 NCS RESTRAINTS STATISTICS
REMARK 3 NUMBER OF DIFFERENT NCS GROUPS : NULL
REMARK 3
REMARK 3 TLS DETAILS
REMARK 3 NUMBER OF TLS GROUPS : NULL
REMARK 3
REMARK 3 BULK SOLVENT MODELLING.
REMARK 3 METHOD USED : MASK
REMARK 3 PARAMETERS FOR MASK CALCULATION
REMARK 3 VDW PROBE RADIUS : 1.20
REMARK 3 ION PROBE RADIUS : 0.80
REMARK 3 SHRINKAGE RADIUS : 0.80
REMARK 3
REMARK 3 OTHER REFINEMENT REMARKS: HYDROGENS HAVE BEEN USED IF PRESENT IN
REMARK 3 THE INPUT
REMARK 4
REMARK 4 4HXK 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_1000076045.
REMARK 200
REMARK 200 EXPERIMENTAL DETAILS
REMARK 200 EXPERIMENT TYPE : X-RAY DIFFRACTION
REMARK 200 DATE OF DATA COLLECTION : 13-MAR-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) : 1.610
REMARK 200 RESOLUTION RANGE LOW (A) : 30.270
REMARK 200 REJECTION CRITERIA (SIGMA(I)) : -3.000
REMARK 200
REMARK 200 OVERALL.
REMARK 200 COMPLETENESS FOR RANGE (%) : 98.9
REMARK 200 DATA REDUNDANCY : NULL
REMARK 200 R MERGE (I) : 0.05100
REMARK 200 R SYM (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR THE DATA SET : 14.8400
REMARK 200
REMARK 200 IN THE HIGHEST RESOLUTION SHELL.
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE HIGH (A) : 1.61
REMARK 200 HIGHEST RESOLUTION SHELL, RANGE LOW (A) : 1.65
REMARK 200 COMPLETENESS FOR SHELL (%) : 99.5
REMARK 200 DATA REDUNDANCY IN SHELL : NULL
REMARK 200 R MERGE FOR SHELL (I) : 0.37500
REMARK 200 R SYM FOR SHELL (I) : NULL
REMARK 200 <I/SIGMA(I)> FOR SHELL : 4.220
REMARK 200
REMARK 200 DIFFRACTION PROTOCOL: SINGLE WAVELENGTH
REMARK 200 METHOD USED TO DETERMINE THE STRUCTURE: MOLECULAR REPLACEMENT
REMARK 200 SOFTWARE USED: PHASER 2.3.0
REMARK 200 STARTING MODEL: NULL
REMARK 200
REMARK 200 REMARK: NULL
REMARK 280
REMARK 280 CRYSTAL
REMARK 280 SOLVENT CONTENT, VS (%): 39.12
REMARK 280 MATTHEWS COEFFICIENT, VM (ANGSTROMS**3/DA): 2.02
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 16.13500
REMARK 290 SMTRY2 2 0.000000 -1.000000 0.000000 0.00000
REMARK 290 SMTRY3 2 0.000000 0.000000 1.000000 39.36000
REMARK 290 SMTRY1 3 -1.000000 0.000000 0.000000 0.00000
REMARK 290 SMTRY2 3 0.000000 1.000000 0.000000 23.67500
REMARK 290 SMTRY3 3 0.000000 0.000000 -1.000000 39.36000
REMARK 290 SMTRY1 4 1.000000 0.000000 0.000000 16.13500
REMARK 290 SMTRY2 4 0.000000 -1.000000 0.000000 23.67500
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 800
REMARK 800 SITE
REMARK 800 SITE_IDENTIFIER: AC1
REMARK 800 EVIDENCE_CODE: SOFTWARE
REMARK 800 SITE_DESCRIPTION: BINDING SITE FOR RESIDUE 1AJ A 201
REMARK 900
REMARK 900 RELATED ENTRIES
REMARK 900 RELATED ID: 4HXL 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 4HXK A 44 167 UNP O60885 BRD4_HUMAN 44 167
SEQADV 4HXK 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 1AJ A 201 16
HETNAM 1AJ 6,7-DIHYDROTHIENO[3,2-C]PYRIDIN-5(4H)-YL(1H-IMIDAZOL-1-
HETNAM 2 1AJ YL)METHANONE
FORMUL 2 1AJ C11 H11 N3 O S
FORMUL 3 HOH *98(H2 O)
HELIX 1 1 THR A 60 VAL A 69 1 10
HELIX 2 2 VAL A 69 LYS A 76 1 8
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 GLU A 163 1 20
SITE 1 AC1 8 PRO A 82 PHE A 83 VAL A 87 TYR A 97
SITE 2 AC1 8 CYS A 136 TYR A 139 ASN A 140 HOH A 345
CRYST1 32.270 47.350 78.720 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 0.030989 0.000000 0.000000 0.00000
SCALE2 0.000000 0.021119 0.000000 0.00000
SCALE3 0.000000 0.000000 0.012703 0.00000
(ATOM LINES ARE NOT SHOWN.)
END