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- PDB-5dx4: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5dx4
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with benzo[cd]indol-2(1H)-one ligand
ComponentsBromodomain-containing protein 4
KeywordsSIGNALING PROTEIN/INHIBITOR / BRD4 / Bromodomain / Four Alpha Helices / SIGNALING PROTEIN-INHIBITOR complex
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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II ...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 / RNA polymerase II CTD heptapeptide repeat kinase activity / histone reader activity / condensed nuclear chromosome / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / 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 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / Brdt, bromodomain, repeat I / Brdt, bromodomain, repeat II / NET domain superfamily / NET domain profile. / : / 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
Chem-E0C / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhang, Y. / Song, M. / Liu, Z. / Xue, X. / Xu, Y.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Benzo[cd]indol-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation
Authors: Xue, X. / Zhang, Y. / Liu, Z. / Song, M. / Xing, Y. / Xiang, Q. / Wang, Z. / Tu, Z. / Zhou, Y. / Ding, K. / Xu, Y.
History
DepositionSep 23, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2016Group: Data collection / Database references
Revision 1.2Mar 9, 2016Group: Database references
Revision 1.3Nov 8, 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 / citation / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)15,6274
Polymers15,0251
Non-polymers6023
Water46826
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area360 Å2
ΔGint5 kcal/mol
Surface area7600 Å2
Unit cell
Length a, b, c (Å)38.830, 48.440, 77.420
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15025.235 Da / Num. of mol.: 1 / Fragment: N-TERMINAL BROMODOMAIN, UNP RESIDUES 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pET24a / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-E0C / 5-bromo-N-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)-2-methoxybenzenesulfonamide


Mass: 461.329 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H17BrN2O4S
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


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


Mass: 18.015 Da / Num. of mol.: 26 / 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: 2.45 Å3/Da / Density % sol: 49.84 %
Description: THE ENTRY CONTAINS FRIEDEL PAIRS IN F_PLUS/MINUS COLUMNS.
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 20% PEG3350, 0.2M NaNO3, 0.1M HEPES, 10% EtGhly,pH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 7, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.3→77.42 Å / Num. obs: 6577 / % possible obs: 96.3 % / Redundancy: 4.5 % / CC1/2: 0.989 / Rmerge(I) obs: 0.114 / Net I/σ(I): 9.2 / Num. measured all: 29759 / Scaling rejects: 110
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2% possible all
2.3-2.384.30.1885.126586170.96995.3
8.91-77.423.70.08612.24971350.97390

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
Aimless0.5.14data scaling
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 2.3→41.06 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.913 / SU B: 5.78 / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.408 / ESU R Free: 0.241 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY. SF FILE CONTAINS FRIEDEL PAIRS UNDER I/F_MINUS AND I/F_PLUS COLUMNS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2391 313 4.8 %RANDOM
Rwork0.2154 ---
obs0.2166 6237 95.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 68.87 Å2 / Biso mean: 25.229 Å2 / Biso min: 10.77 Å2
Baniso -1Baniso -2Baniso -3
1-4.49 Å20 Å20 Å2
2---1.19 Å20 Å2
3----3.3 Å2
Refinement stepCycle: final / Resolution: 2.3→41.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1048 0 36 26 1110
Biso mean--24.54 20.78 -
Num. residues----126
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.021125
X-RAY DIFFRACTIONr_bond_other_d0.0030.021065
X-RAY DIFFRACTIONr_angle_refined_deg1.3022.0051534
X-RAY DIFFRACTIONr_angle_other_deg0.9313.0052458
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4935127
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.28425.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.09615194
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.48153
X-RAY DIFFRACTIONr_chiral_restr0.0660.2159
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211258
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02255
X-RAY DIFFRACTIONr_mcbond_it1.1022.454508
X-RAY DIFFRACTIONr_mcbond_other1.1012.446507
X-RAY DIFFRACTIONr_mcangle_it1.83.662635
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.226 21 -
Rwork0.163 432 -
all-453 -
obs--94.18 %

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