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- PDB-3mxf: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 3mxf
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JQ1
ComponentsBromodomain-containing protein 4BRD4
KeywordsCELL CYCLE / Bromodomain-containing protein 4 isoform long / BRD4 / Bromodomain containing protein 4 / CAP / HUNK1 / MCAP / Mitotic chromosome associated protein / JQ1 / betsoff1 / Structural Genomics Consortium / SGC
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / positive regulation of T-helper 17 cell lineage commitment / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / lysine-acetylated histone binding / p53 binding / chromosome / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus
Similarity search - Function
Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
IODIDE ION / Chem-JQ1 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Qi, J. / Keates, T. / Felletar, I. / Fedorov, O. / Muniz, J. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. ...Filippakopoulos, P. / Picaud, S. / Qi, J. / Keates, T. / Felletar, I. / Fedorov, O. / Muniz, J. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Weigelt, J. / Bountra, C. / Bradner, J.E. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Nature / Year: 2010
Title: Selective inhibition of BET bromodomains.
Authors: Filippakopoulos, P. / Qi, J. / Picaud, S. / Shen, Y. / Smith, W.B. / Fedorov, O. / Morse, E.M. / Keates, T. / Hickman, T.T. / Felletar, I. / Philpott, M. / Munro, S. / McKeown, M.R. / Wang, ...Authors: Filippakopoulos, P. / Qi, J. / Picaud, S. / Shen, Y. / Smith, W.B. / Fedorov, O. / Morse, E.M. / Keates, T. / Hickman, T.T. / Felletar, I. / Philpott, M. / Munro, S. / McKeown, M.R. / Wang, Y. / Christie, A.L. / West, N. / Cameron, M.J. / Schwartz, B. / Heightman, T.D. / La Thangue, N. / French, C.A. / Wiest, O. / Kung, A.L. / Knapp, S. / Bradner, J.E.
History
DepositionMay 7, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Mar 28, 2012Group: Structure summary
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,9497
Polymers15,0991
Non-polymers8496
Water3,747208
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.800, 44.760, 78.390
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsMonomer

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Bromodomain-containing protein 4 / BRD4 / Protein HUNK1


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1, Mcap / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885

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Non-polymers , 5 types, 214 molecules

#2: Chemical ChemComp-JQ1 / (6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium / JQ1


Mass: 457.996 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26ClN4O2S / Comment: inhibitor*YM
#3: Chemical ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 208 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.14 Å3/Da / Density % sol: 42.47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.2M NaI 0.1M BTProp pH 8.5 20% PEG3350 10% EtGhly, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.542 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Mar 3, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.542 Å / Relative weight: 1
ReflectionResolution: 1.6→26.828 Å / Num. all: 17716 / Num. obs: 17663 / % possible obs: 99.7 % / Redundancy: 4.1 % / Biso Wilson estimate: 14.5 Å2 / Rmerge(I) obs: 0.046 / Rsym value: 0.046 / Net I/σ(I): 18.6
Reflection shellResolution: 1.6→1.69 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.137 / Mean I/σ(I) obs: 6.9 / Num. unique all: 2467 / Rsym value: 0.16 / % possible all: 98.5

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 55.02 / Model details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å26.83 Å
Translation2.5 Å26.83 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
CrystalCleardata collection
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2OSS

2oss


Resolution: 1.6→26.83 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.952 / WRfactor Rfree: 0.185 / WRfactor Rwork: 0.15 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.91 / SU B: 2.208 / SU ML: 0.045 / SU R Cruickshank DPI: 0.083 / SU Rfree: 0.085 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.085 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.184 894 5.1 %RANDOM
Rwork0.15 ---
all0.151 17687 --
obs0.151 17609 99.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 63.21 Å2 / Biso mean: 14.011 Å2 / Biso min: 4.46 Å2
Baniso -1Baniso -2Baniso -3
1-0.42 Å20 Å20 Å2
2---0.12 Å20 Å2
3----0.3 Å2
Refinement stepCycle: LAST / Resolution: 1.6→26.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1059 0 48 208 1315
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0221150
X-RAY DIFFRACTIONr_bond_other_d0.0010.02785
X-RAY DIFFRACTIONr_angle_refined_deg1.6982.011565
X-RAY DIFFRACTIONr_angle_other_deg0.9653.0011924
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0065126
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.9932655
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.50615202
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.292153
X-RAY DIFFRACTIONr_chiral_restr0.0990.2166
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211218
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02196
X-RAY DIFFRACTIONr_mcbond_it1.7953650
X-RAY DIFFRACTIONr_mcbond_other0.5513243
X-RAY DIFFRACTIONr_mcangle_it2.80251075
X-RAY DIFFRACTIONr_scbond_it3.968500
X-RAY DIFFRACTIONr_scangle_it5.32311490
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.337 58 -
Rwork0.292 1152 -
all-1210 -
obs--96.49 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.9205-0.13591.04361.4061-0.90631.9367-0.0298-0.1096-0.00480.09580.01390.0328-0.0944-0.09510.01590.01010.00290.00850.03850.00250.024827.077628.327115.3916
20.71650.05990.44491.09790.69041.5437-0.00660.0004-0.0210.02650.0152-0.00690.00620.0367-0.00860.0012-0.0015-0.00230.00830.00960.013231.436923.17145.7649
35.89563.84365.235513.460914.790335.644-0.0735-0.26470.18670.1111-0.0107-0.1462-0.4566-0.17790.08420.05320.0053-0.00440.01860.00280.104828.752543.242410.4958
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 77
2X-RAY DIFFRACTION2A78 - 158
3X-RAY DIFFRACTION3A159 - 168

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