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- PDB-7mr6: Crystal structure of the first bromodomain (BD1) of human BRD4 bo... -

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Basic information

Entry
Database: PDB / ID: 7mr6
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 bound to GXH-II-082
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / BRD4 / BRD / BET
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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 / chromatin / 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 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-ZMV / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsChan, A. / Schonbrunn, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health & Human Development (NIH/NICHD)1U54HD093540 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.
Authors: Guan, X. / Cheryala, N. / Karim, R.M. / Chan, A. / Berndt, N. / Qi, J. / Georg, G.I. / Schonbrunn, E.
History
DepositionMay 7, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 3, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,6373
Polymers30,1992
Non-polymers1,4381
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-8 kcal/mol
Surface area14450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)30.230, 40.350, 57.200
Angle α, β, γ (deg.)100.230, 104.690, 90.290
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 15099.380 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: O60885
#2: Chemical ChemComp-ZMV / N,N'-[(1,16-dioxo-4,7,10,13-tetraoxahexadecane-1,16-diyl)di(piperidine-1,4-diyl)]bis{4-[(4-{4-chloro-3-[(2-methylpropane-2-sulfonyl)amino]anilino}-5-methylpyrimidin-2-yl)amino]-2-fluorobenzamide}


Mass: 1438.493 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C66H84Cl2F2N14O12S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.2 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Sodium chloride, 0.1 M BIS-TRIS pH 5.5, 25% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 20, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→29.544 Å / Num. obs: 19818 / % possible obs: 90.2 % / Redundancy: 3.316 % / CC1/2: 0.984 / Rmerge(I) obs: 0.127 / Rrim(I) all: 0.151 / Χ2: 0.823 / Net I/σ(I): 6.58 / Num. measured all: 65715 / Scaling rejects: 743
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
1.85-1.91.9260.32322176160911300.8090.45770.2
1.9-1.953.3250.472.734858159314610.7690.5691.7
1.95-2.013.3750.3743.314998159714810.8570.44492.7
2.01-2.073.3620.33.84512144113420.9090.35693.1
2.07-2.143.390.264.614563147813460.9160.30991.1
2.14-2.213.3280.2245.364273140312840.9120.26891.5
2.21-2.293.2720.2045.653969135912130.9140.24589.3
2.29-2.393.2650.1776.123523130010790.9420.21183
2.39-2.493.4230.1816.824008124311710.9290.21794.2
2.49-2.623.4140.167.113831118111220.9510.19295
2.62-2.763.4380.1477.833685114810720.9520.17593.4
2.76-2.933.480.1448.61346610599960.9470.17294.1
2.93-3.133.4860.1249.16329410209450.9670.14792.6
3.13-3.383.4510.1079.8928689618310.9740.12786.5
3.38-3.73.4970.09510.826408237550.980.11391.7
3.7-4.143.5150.09311.2626507897540.9790.1195.6
4.14-4.783.5330.08411.7123536996660.9810.195.3
4.78-5.853.4940.08911.3718875795400.9850.10493.3
5.85-8.273.4680.0811.4313634533930.9910.09486.8
8.27-29.5443.3670.06911.837982432370.9940.0897.5

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Processing

Software
NameVersionClassification
PHENIX1.11.1-2575_3260refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.85→29.544 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 2.01 / Phase error: 30.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.26 1099 5.55 %
Rwork0.2042 18712 -
obs0.2072 19811 90.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 58.83 Å2 / Biso mean: 23.7302 Å2 / Biso min: 11.14 Å2
Refinement stepCycle: final / Resolution: 1.85→29.544 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 98 232 2454
Biso mean--30.59 28.94 -
Num. residues----254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082289
X-RAY DIFFRACTIONf_angle_d1.0313122
X-RAY DIFFRACTIONf_chiral_restr0.049318
X-RAY DIFFRACTIONf_plane_restr0.007396
X-RAY DIFFRACTIONf_dihedral_angle_d9.171389
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.85-1.93420.39831200.301205479
1.9342-2.03610.35511420.2863241093
2.0361-2.16370.29661400.2415237692
2.1637-2.33070.28231360.2197231690
2.3307-2.56510.28371380.2129235091
2.5651-2.9360.25161430.2003243094
2.936-3.69790.22811370.1801233590
3.6979-29.5440.2181430.1733244194

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