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- PDB-6yqn: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6yqn
TitleCrystal structure of the first bromodomain of human BRD4 in complex with the dual inhibitor TW9
ComponentsBromodomain-containing protein 4
KeywordsGENE REGULATION / bromodomain / BRD4(BD1) / dual bromodomain HDAC inhibitor / structural genomics consortium / SGC
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 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 / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-P8T / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.05 Å
AuthorsJoerger, A.C. / Balourdas, D.I. / Weiser, T. / Chatterjee, D. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Int.J.Cancer / Year: 2020
Title: Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma.
Authors: Zhang, X. / Zegar, T. / Weiser, T. / Hamdan, F.H. / Berger, B.T. / Lucas, R. / Balourdas, D.I. / Ladigan, S. / Cheung, P.F. / Liffers, S.T. / Trajkovic-Arsic, M. / Scheffler, B. / Joerger, A. ...Authors: Zhang, X. / Zegar, T. / Weiser, T. / Hamdan, F.H. / Berger, B.T. / Lucas, R. / Balourdas, D.I. / Ladigan, S. / Cheung, P.F. / Liffers, S.T. / Trajkovic-Arsic, M. / Scheffler, B. / Joerger, A.C. / Hahn, S.A. / Johnsen, S.A. / Knapp, S. / Siveke, J.T.
History
DepositionApr 17, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 18, 2020Group: Database references / Derived calculations / Structure summary
Category: chem_comp / citation ...chem_comp / citation / citation_author / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _citation.country ..._chem_comp.name / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)15,8344
Polymers15,0991
Non-polymers7343
Water2,648147
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area440 Å2
ΔGint6 kcal/mol
Surface area7050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)37.254, 44.338, 78.256
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Production host: Escherichia coli (E. coli) / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-P8T / ~{N}-(2-aminophenyl)-4-[2-[(9~{S})-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^{2,6}]t rideca-2(6),4,7,10,12-pentaen-9-yl]ethanoylamino]benzamide / TW9


Mass: 610.128 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H28ClN7O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 2.14 Å3/Da / Density % sol: 42.53 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: Protein solution: 10 mg/ml in 10 mM HEPES, pH 7.5, 150 mM NaCl, 0.5 mM TCEP, and 5% glycerol. 50 mM stock solution of TW12 in DMSO added to give a final inhibitor concentration 1.5 mM. ...Details: Protein solution: 10 mg/ml in 10 mM HEPES, pH 7.5, 150 mM NaCl, 0.5 mM TCEP, and 5% glycerol. 50 mM stock solution of TW12 in DMSO added to give a final inhibitor concentration 1.5 mM. Reservoir buffer: 24% PEG 3350, 0.1 M sodium formate, 15% ethylene glycol and 0.1 M bis-Tris-propane pH 7.3. Ratio protein/reservoir solution = 2:1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.70848 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 30, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.70848 Å / Relative weight: 1
ReflectionResolution: 1.05→78.3 Å / Num. obs: 61370 / % possible obs: 100 % / Redundancy: 11.6 % / Biso Wilson estimate: 9.65991112921 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.084 / Net I/σ(I): 14.3
Reflection shellResolution: 1.05→1.07 Å / Rmerge(I) obs: 0.69 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 3002 / CC1/2: 0.896

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3MXF

3mxf


Resolution: 1.05→39.15 Å / SU ML: 0.0701034166058 / Cross valid method: FREE R-VALUE / σ(F): 1.33737477503 / Phase error: 18.2222547652
RfactorNum. reflection% reflection
Rfree0.176224999275 3095 5.05223636957 %
Rwork0.164199975376 --
obs0.164805061865 61260 99.9396381552 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 14.181153913 Å2
Refinement stepCycle: LAST / Resolution: 1.05→39.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1019 0 35 147 1201
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004972518558731141
X-RAY DIFFRACTIONf_angle_d0.821959391781570
X-RAY DIFFRACTIONf_chiral_restr0.0741496552007170
X-RAY DIFFRACTIONf_plane_restr0.00545915163667224
X-RAY DIFFRACTIONf_dihedral_angle_d10.8622616378454
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.05-1.06640.2763423056341200.2562290216762620X-RAY DIFFRACTION99.8178506375
1.0664-1.08390.2592493671551540.2387108501962594X-RAY DIFFRACTION99.8909487459
1.0839-1.10260.2271447229051440.2171591334172605X-RAY DIFFRACTION99.8909883721
1.1026-1.12270.2126406738121600.2062152425052574X-RAY DIFFRACTION99.8174516247
1.1227-1.14420.1741372483851480.1918989656692596X-RAY DIFFRACTION99.9635701275
1.1442-1.16760.2379547917441380.191068818742647X-RAY DIFFRACTION99.7850232891
1.1676-1.1930.2093490181351320.1867620392722589X-RAY DIFFRACTION99.8532110092
1.193-1.22070.1961426819481300.1864638457392614X-RAY DIFFRACTION99.9271667881
1.2207-1.25130.2032028563751250.1680765505692639X-RAY DIFFRACTION99.9276934201
1.2513-1.28510.1674516418431430.1384846664542646X-RAY DIFFRACTION100
1.2851-1.32290.1741830220041350.1560650589622603X-RAY DIFFRACTION99.9634903249
1.3229-1.36560.1781635149641410.1518134492942622X-RAY DIFFRACTION99.9638205499
1.3656-1.41440.1718192825841370.1469383161082646X-RAY DIFFRACTION100
1.4144-1.47110.153515134861430.1388975024192619X-RAY DIFFRACTION99.9638074557
1.4711-1.5380.155506959031640.1338381644442616X-RAY DIFFRACTION100
1.538-1.61910.142855829491360.1344086883152651X-RAY DIFFRACTION100
1.6191-1.72060.1638797200951260.1440027449082667X-RAY DIFFRACTION100
1.7206-1.85340.1611600489471490.1497291461672669X-RAY DIFFRACTION100
1.8534-2.03990.1587935115191400.1535283504182661X-RAY DIFFRACTION100
2.0399-2.33510.174551709471330.1581220619612716X-RAY DIFFRACTION100
2.3351-2.94180.1952121182671620.1739568229892696X-RAY DIFFRACTION100
2.9418-39.150.1646417165161350.1712712056772875X-RAY DIFFRACTION99.9335989376

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