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- PDB-5cp5: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5cp5
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-EB0 / NITRATE ION / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 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)17,2624
Polymers16,7671
Non-polymers4943
Water1,54986
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area390 Å2
ΔGint4 kcal/mol
Surface area7440 Å2
Unit cell
Length a, b, c (Å)35.670, 47.340, 77.580
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: 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-EB0 / 1-ethyl-N-(4-fluorophenyl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide


Mass: 370.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15FN2O3S
#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-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 37.03 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG3350, 0.2M (NH4)2SO4, 0.1M HEPES, 10% EtGhly, pH7.5

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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: 1.79→47.34 Å / Num. obs: 11567 / % possible obs: 89 % / Redundancy: 11.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.023 / Net I/σ(I): 21.2 / Num. measured all: 136769 / Scaling rejects: 218
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
1.79-1.8310.90.2678.381057460.9850.084100
8.95-47.349.90.06328.913481360.9980.01999.7

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Processing

Software
NameVersionClassification
Aimless0.5.12data scaling
REFMAC5.8.0124refinement
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.79→40.41 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.914 / SU B: 2.741 / SU ML: 0.087 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.16 / ESU R Free: 0.15 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 579 5 %RANDOM
Rwork0.1943 ---
obs0.1966 10948 89.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 54.24 Å2 / Biso mean: 20.832 Å2 / Biso min: 11.47 Å2
Baniso -1Baniso -2Baniso -3
1-1.64 Å20 Å20 Å2
2---0.46 Å20 Å2
3----1.17 Å2
Refinement stepCycle: final / Resolution: 1.79→40.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1057 0 34 86 1177
Biso mean--22.08 28.67 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.021123
X-RAY DIFFRACTIONr_bond_other_d0.0030.021063
X-RAY DIFFRACTIONr_angle_refined_deg1.4892.0031529
X-RAY DIFFRACTIONr_angle_other_deg0.9743.0042453
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7425126
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.8425.47253
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.06415193
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.257154
X-RAY DIFFRACTIONr_chiral_restr0.0720.2158
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211249
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02257
X-RAY DIFFRACTIONr_mcbond_it1.2691.905507
X-RAY DIFFRACTIONr_mcbond_other1.2591.902506
X-RAY DIFFRACTIONr_mcangle_it1.9942.847632
LS refinement shellResolution: 1.79→1.836 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.296 49 -
Rwork0.203 872 -
all-921 -
obs--99.89 %

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