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- PDB-5cs8: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5cs8
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 / BROMODOMAIN BINDING INHIBITOR / 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-EB8 / NITRATE ION / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / 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 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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,76410
Polymers16,7671
Non-polymers9979
Water90150
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint5 kcal/mol
Surface area8850 Å2
Unit cell
Length a, b, c (Å)34.960, 47.220, 78.080
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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 44-168
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

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Non-polymers , 5 types, 59 molecules

#2: Chemical ChemComp-EB8 / methyl 2-[(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)sulfamoyl]benzoate


Mass: 410.443 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N2O5S
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / 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: 1.93 Å3/Da / Density % sol: 36.38 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8.3
Details: 20% PEG3350, 0.2M NaNO3, 0.1M HEPES, 10% EtGhly, pH 8.3

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Type: OTHER / Wavelength: 0.97852 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 22, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 1.62→78.08 Å / Num. obs: 15614 / % possible obs: 91.1 % / Redundancy: 5.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.026 / Net I/σ(I): 15 / Num. measured all: 87080 / Scaling rejects: 91
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
1.62-1.645.80.1975.447348170.9840.08699.8
8.86-78.085.10.06126.97031390.9920.02899.7

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Processing

Software
NameVersionClassification
Aimless0.5.9data scaling
REFMAC5.8.0123refinement
PDB_EXTRACT3.15data extraction
MOSFLMdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.62→40.41 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.954 / SU B: 2.173 / SU ML: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.114 / ESU R Free: 0.105 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2152 762 4.9 %RANDOM
Rwork0.1894 ---
obs0.1907 14810 90.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 71.25 Å2 / Biso mean: 25.296 Å2 / Biso min: 14.56 Å2
Baniso -1Baniso -2Baniso -3
1-4.39 Å20 Å2-0 Å2
2---2.21 Å20 Å2
3----2.18 Å2
Refinement stepCycle: final / Resolution: 1.62→40.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1115 0 67 50 1232
Biso mean--30.63 28.97 -
Num. residues----133
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0191213
X-RAY DIFFRACTIONr_bond_other_d0.0040.021148
X-RAY DIFFRACTIONr_angle_refined_deg1.6341.9991641
X-RAY DIFFRACTIONr_angle_other_deg1.023.0052645
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8715132
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.3192558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.47615200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.394154
X-RAY DIFFRACTIONr_chiral_restr0.0950.2168
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211326
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02282
X-RAY DIFFRACTIONr_mcbond_it1.6882.269531
X-RAY DIFFRACTIONr_mcbond_other1.6872.268530
X-RAY DIFFRACTIONr_mcangle_it2.3843.393662
LS refinement shellResolution: 1.617→1.659 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 59 -
Rwork0.237 1185 -
all-1244 -
obs--99.36 %

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