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- PDB-7mr7: Crystal structure of the first bromodomain (BD1) of human BRD4 bo... -

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Basic information

Entry
Database: PDB / ID: 7mr7
TitleCrystal structure of the first bromodomain (BD1) of human BRD4 bound to GXH-II-075
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / Bromosporine / BRD4 / BRD / BET
Function / homology
Function and homology information


RNA polymerase II C-terminal domain binding / P-TEFb complex binding / negative regulation of DNA damage checkpoint / 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 / P-TEFb complex binding / negative regulation of DNA damage checkpoint / 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 / histone binding / Potential therapeutics for SARS / transcription coactivator activity / 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, conserved site ...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, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily
Similarity search - Domain/homology
Chem-ZN1 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 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 11, 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)31,7606
Polymers30,1992
Non-polymers1,5614
Water4,107228
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)30.281, 39.895, 57.456
Angle α, β, γ (deg.)100.030, 104.500, 90.180
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) / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-ZN1 / 4-[(4-{4-chloro-3-[(2-methylpropane-2-sulfonyl)amino]anilino}-5-methylpyrimidin-2-yl)amino]-2-fluoro-N-[1-(14-{3-[(2-{3-fluoro-4-[(piperidin-4-yl)carbamoyl]anilino}-5-methylpyrimidin-4-yl)amino]-5-[(2-methylpropane-2-sulfonyl)amino]phenyl}-14-oxo-4,7,10-trioxa-13-azatetradecanan-1-oyl)piperidin-4-yl]benzamide


Mass: 1375.010 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C64H82ClF2N15O11S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2.19 Å3/Da / Density % sol: 43.8 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Ammonium sulfate,0.1 M HEPES pH 7.5, 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: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 9, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.15→54.71 Å / Num. obs: 55324 / % possible obs: 61.1 % / Redundancy: 1.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.038 / Rpim(I) all: 0.038 / Rrim(I) all: 0.054 / Net I/σ(I): 4.6 / Num. measured all: 96130
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.15-1.211.40.905138210200.4160.9051.280.57.7
3.64-54.711.80.023457325640.9970.0230.03310.289.7

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.18.2-3874_3874refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3MXF

3mxf


Resolution: 1.4→39.24 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.97 / Phase error: 20.58 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1938 2106 4.62 %
Rwork0.1765 43485 -
obs0.1773 45591 90.37 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 55.63 Å2 / Biso mean: 20.1716 Å2 / Biso min: 9.22 Å2
Refinement stepCycle: final / Resolution: 1.4→39.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2098 0 107 228 2433
Biso mean--26.57 25.51 -
Num. residues----251
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.4-1.430.26411460.26582903304990
1.43-1.470.24681300.2262910304092
1.47-1.510.23921310.21132963309491
1.51-1.550.25061410.20862931307292
1.55-1.60.20171230.18952998312192
1.6-1.660.2011370.18232982311993
1.66-1.730.2311400.18112972311292
1.73-1.80.20531730.17982915308892
1.8-1.90.22431580.1792933309192
1.9-2.020.1911210.17492910303191
2.02-2.170.16721400.1682857299789
2.17-2.390.1851260.17442821294788
2.39-2.740.18771460.18342797294387
2.74-3.450.20811510.18092727287886
3.45-39.240.1621430.15192866300989
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.12871.00990.31216.8129-1.88085.6211-0.162-0.0823-0.5353-0.2941-0.034-0.1180.77670.14070.25470.23190.03060.00720.1214-0.01280.1971-3.9384-9.3905-18.2839
21.5616-0.4269-0.79071.1443-0.84652.5068-0.1349-0.09420.0363-0.1162-0.2321-0.24260.00770.50010.17090.15610.00850.02590.16930.05740.15124.72379.5872-17.6508
30.9722-0.239-0.21871.18890.37631.9199-0.0141-0.094-0.08860.0971-0.08440.02730.23480.03730.12070.10380.00130.00350.11010.00670.1192-5.1525-1.6495-12.8415
42.44911.3178-0.0862.1750.44462.03990.0202-0.06350.18820.0355-0.09540.1189-0.1143-0.12650.04670.09530.0283-0.01350.1076-0.00330.12-9.83459.1144-11.4864
53.76480.09480.10746.21271.78653.27460.0374-0.0231-0.39730.3311-0.13630.1810.3783-0.31350.16570.1734-0.0548-0.00410.13960.04390.1725-17.34012.050422.7775
61.89930.2942-1.60432.7241.65874.04780.0959-0.03430.09450.092-0.33280.26250.0787-0.5040.15740.1677-0.04130.00970.2023-0.0530.207-25.773520.409924.9744
72.4981-1.4573-1.80214.65694.83515.9401-0.0060.14220.0097-0.0123-0.15920.404-0.4845-0.4465-0.04250.14030.0135-0.01840.1411-0.0140.1743-21.589618.70499.9012
82.0391-0.1440.17892.1987-1.1093.0482-0.00310.0557-0.2737-0.107-0.04820.02260.26960.10730.03660.1111-0.00320.01070.1123-0.00610.1514-9.96654.975212.0088
91.5475-0.4308-1.03431.030.51721.60130.0112-0.00020.10150.0479-0.01510.0582-0.064-0.03930.03560.1139-0.0152-0.00670.10920.00570.1212-13.647614.424519.0776
103.0844-2.8962-2.55362.68282.47663.92680.1378-0.04880.314-0.16370.0222-0.2048-0.3380.1133-0.19070.1588-0.0349-0.00560.10270.00320.1762-12.155323.483412.0039
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 42 through 51 )A42 - 51
2X-RAY DIFFRACTION2chain 'A' and (resid 52 through 76 )A52 - 76
3X-RAY DIFFRACTION3chain 'A' and (resid 77 through 121 )A77 - 121
4X-RAY DIFFRACTION4chain 'A' and (resid 122 through 167 )A122 - 167
5X-RAY DIFFRACTION5chain 'B' and (resid 43 through 52 )B43 - 52
6X-RAY DIFFRACTION6chain 'B' and (resid 53 through 68 )B53 - 68
7X-RAY DIFFRACTION7chain 'B' and (resid 69 through 76 )B69 - 76
8X-RAY DIFFRACTION8chain 'B' and (resid 77 through 106 )B77 - 106
9X-RAY DIFFRACTION9chain 'B' and (resid 107 through 144 )B107 - 144
10X-RAY DIFFRACTION10chain 'B' and (resid 145 through 167 )B145 - 167

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