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

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Basic information

Entry
Database: PDB / ID: 5cpe
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 / Transcription-transcr / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome ...RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / histone H4 reader activity / host-mediated suppression of viral transcription / positive regulation of G2/M transition of mitotic cell cycle / positive regulation of T-helper 17 cell lineage commitment / : / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / transcription coregulator activity / positive regulation of transcription elongation by RNA polymerase II / p53 binding / chromosome / regulation of inflammatory response / histone binding / Potential therapeutics for SARS / transcription coactivator activity / positive regulation of canonical NF-kappaB signal transduction / transcription cis-regulatory region binding / chromatin remodeling / protein serine/threonine kinase activity / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / chromatin / 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 / bromo domain / Bromodomain / Bromodomain (BrD) profile. / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-EB2 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.62 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
DepositionJul 21, 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 1.3Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / diffrn_radiation_wavelength / 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)17,2644
Polymers16,7671
Non-polymers4973
Water2,126118
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area440 Å2
ΔGint6 kcal/mol
Surface area7910 Å2
Unit cell
Length a, b, c (Å)30.060, 45.820, 47.740
Angle α, β, γ (deg.)90.000, 96.720, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 16767.326 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-EB2 / N-cycloheptyl-1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide


Mass: 372.481 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N2O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 1.95 Å3/Da / Density % sol: 36.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 20% PEG3350, 0.2M NaNO3, 0.1M HEPES,10% EtGhly, pH7.2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Type: OTHER / Wavelength: 0.97776 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 27, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97776 Å / Relative weight: 1
ReflectionResolution: 1.62→47.41 Å / Num. obs: 16363 / % possible obs: 98.5 % / Redundancy: 6.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.02 / Net I/σ(I): 31.5 / Num. measured all: 103425 / Scaling rejects: 169
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2Rpim(I) all% possible all
1.62-1.646.50.08317.554238350.9950.03598
8.7-47.416.40.06855.17811220.990.02899.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0124refinement
Aimless0.5.9data scaling
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementResolution: 1.62→47.41 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.951 / SU B: 1.326 / SU ML: 0.048 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.09 / ESU R Free: 0.087 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1868 787 4.8 %RANDOM
Rwork0.1593 ---
obs0.1607 15568 98.3 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 49.56 Å2 / Biso mean: 15.348 Å2 / Biso min: 6.91 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å20 Å2-0.12 Å2
2---0.03 Å2-0 Å2
3---0.25 Å2
Refinement stepCycle: final / Resolution: 1.62→47.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1082 0 34 118 1234
Biso mean--16.44 23.91 -
Num. residues----130
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.021161
X-RAY DIFFRACTIONr_bond_other_d0.0040.021120
X-RAY DIFFRACTIONr_angle_refined_deg1.6571.9991584
X-RAY DIFFRACTIONr_angle_other_deg1.053.0072589
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1835133
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.31425.45555
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.82715200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.062154
X-RAY DIFFRACTIONr_chiral_restr0.3630.2167
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211282
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02262
X-RAY DIFFRACTIONr_mcbond_it1.0971.323523
X-RAY DIFFRACTIONr_mcbond_other1.0791.317522
X-RAY DIFFRACTIONr_mcangle_it1.7871.973653
LS refinement shellResolution: 1.616→1.658 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.189 52 -
Rwork0.144 1163 -
all-1215 -
obs--98.38 %

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