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

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Basic information

Entry
Database: PDB / ID: 5crm
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 II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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-EB5 / NITRATE ION / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.99 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 23, 2015Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jan 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2016Group: 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)17,5068
Polymers16,7671
Non-polymers7397
Water1,27971
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1080 Å2
ΔGint8 kcal/mol
Surface area8560 Å2
Unit cell
Length a, b, c (Å)34.490, 47.310, 77.980
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 16767.326 Da / Num. of mol.: 1 / Fragment: N-TERMINAL BROMODOMAIN, UNP RESIDUES 44-165
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

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Non-polymers , 6 types, 78 molecules

#2: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#3: Chemical ChemComp-EB5 / N,1-diethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide


Mass: 304.364 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H16N2O3S
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


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


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 1.91 Å3/Da / Density % sol: 35.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 20% PEG3350, 0.2M NaNO3, 0.1M HEPES, 10% EtGhly, PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 0.97923 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97923 Å / Relative weight: 1
ReflectionResolution: 1.99→47.31 Å / Num. obs: 8601 / % possible obs: 92.9 % / Redundancy: 5.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.048 / Rpim(I) all: 0.022 / Net I/σ(I): 24.5 / Num. measured all: 50862 / Scaling rejects: 132
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
1.99-2.0460.112.637726330.9940.04499.3
9.12-47.314.80.03231.35901230.9990.01594.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
Aimless0.5.12data scaling
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.99→40.45 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.938 / SU B: 3.305 / SU ML: 0.094 / Cross valid method: THROUGHOUT / ESU R: 0.213 / ESU R Free: 0.162 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20084 437 5.1 %RANDOM
Rwork0.16508 ---
obs0.16695 8128 92.84 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.137 Å2
Baniso -1Baniso -2Baniso -3
1-3.22 Å20 Å2-0 Å2
2---1.65 Å20 Å2
3----1.57 Å2
Refinement stepCycle: LAST / Resolution: 1.99→40.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1115 0 47 71 1233
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.021194
X-RAY DIFFRACTIONr_bond_other_d0.0040.021136
X-RAY DIFFRACTIONr_angle_refined_deg1.4861.9861620
X-RAY DIFFRACTIONr_angle_other_deg1.0123.0042616
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9465132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.5462558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.22415200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.996154
X-RAY DIFFRACTIONr_chiral_restr0.0820.2168
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211311
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02277
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.1151.759531
X-RAY DIFFRACTIONr_mcbond_other1.1161.758530
X-RAY DIFFRACTIONr_mcangle_it1.7892.627662
X-RAY DIFFRACTIONr_mcangle_other1.7872.628663
X-RAY DIFFRACTIONr_scbond_it1.7442.081663
X-RAY DIFFRACTIONr_scbond_other1.7432.088664
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.8593.012959
X-RAY DIFFRACTIONr_long_range_B_refined4.64214.7651421
X-RAY DIFFRACTIONr_long_range_B_other4.64114.8031422
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.99→2.042 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 33 -
Rwork0.15 624 -
obs--98.8 %

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