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- PDB-6cis: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6cis
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JWG047
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/INHIBITOR / Kinase / Inhibitor / BRD4 / TRANSCRIPTION / TRANSCRIPTION-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
NITRATE ION / Chem-X26 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 Å
AuthorsXu, X. / Blacklow, S.C.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P50 GM107618 United States
Leukemia & Lymphoma SocietySCOR 7003-13 United States
CitationJournal: ACS Chem. Biol. / Year: 2018
Title: Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
Authors: Wang, J. / Erazo, T. / Ferguson, F.M. / Buckley, D.L. / Gomez, N. / Munoz-Guardiola, P. / Dieguez-Martinez, N. / Deng, X. / Hao, M. / Massefski, W. / Fedorov, O. / Offei-Addo, N.K. / Park, P. ...Authors: Wang, J. / Erazo, T. / Ferguson, F.M. / Buckley, D.L. / Gomez, N. / Munoz-Guardiola, P. / Dieguez-Martinez, N. / Deng, X. / Hao, M. / Massefski, W. / Fedorov, O. / Offei-Addo, N.K. / Park, P.M. / Dai, L. / DiBona, A. / Becht, K. / Kim, N.D. / McKeown, M.R. / Roberts, J.M. / Zhang, J. / Sim, T. / Alessi, D.R. / Bradner, J.E. / Lizcano, J.M. / Blacklow, S.C. / Qi, J. / Xu, X. / Gray, N.S.
History
DepositionFeb 25, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 3, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: 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)15,7426
Polymers14,8411
Non-polymers9015
Water4,918273
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.890, 41.908, 84.627
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 14841.152 Da / Num. of mol.: 1 / Fragment: residues 44-166
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-X26 / 11-cyclopentyl-5-methyl-2-({4-[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]-2-[(propan-2-yl)oxy]phenyl}amino)-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 652.829 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C37H48N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: NO3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 2.46 Å3/Da / Density % sol: 50.05 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 100mM Sodium Nitrate, 5% Ethylene Glycol, 18% (w/v) PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.51→84.63 Å / Num. obs: 23381 / % possible obs: 99.5 % / Redundancy: 5.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.048 / Rrim(I) all: 0.114 / Net I/σ(I): 13.4
Reflection shellResolution: 1.51→1.54 Å / Redundancy: 5.5 % / Rmerge(I) obs: 1.264 / Mean I/σ(I) obs: 2 / Num. unique obs: 1135 / CC1/2: 0.515 / Rpim(I) all: 0.602 / Rrim(I) all: 1.406 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.7_650refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4WIV

4wiv


Resolution: 1.51→29.776 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 18.98
RfactorNum. reflection% reflection
Rfree0.2156 1144 5.11 %
Rwork0.176 --
obs0.178 22395 95.22 %
Solvent computationShrinkage radii: 0.04 Å / VDW probe radii: 0.4 Å / Bsol: 56.941 Å2 / ksol: 0.422 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.7105 Å20 Å2-0 Å2
2--0.9608 Å20 Å2
3----0.2503 Å2
Refinement stepCycle: LAST / Resolution: 1.51→29.776 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1031 0 64 276 1371
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0111127
X-RAY DIFFRACTIONf_angle_d1.4141535
X-RAY DIFFRACTIONf_dihedral_angle_d14.06436
X-RAY DIFFRACTIONf_chiral_restr0.085161
X-RAY DIFFRACTIONf_plane_restr0.009197
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5101-1.57880.42011390.36792305X-RAY DIFFRACTION84
1.5788-1.6620.27031400.2462454X-RAY DIFFRACTION90
1.662-1.76610.23911420.18752622X-RAY DIFFRACTION95
1.7661-1.90250.1951370.16672687X-RAY DIFFRACTION97
1.9025-2.09390.23181360.15972734X-RAY DIFFRACTION98
2.0939-2.39680.19841530.1612756X-RAY DIFFRACTION99
2.3968-3.01920.18651620.15892795X-RAY DIFFRACTION99
3.0192-29.78150.19521350.16112898X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: 10.9645 Å / Origin y: -0.2411 Å / Origin z: -11.8091 Å
111213212223313233
T0.0425 Å2-0.0037 Å20.0039 Å2-0.046 Å2-0.0007 Å2--0.048 Å2
L0.1618 °20.0015 °2-0.012 °2-0.2308 °20.0412 °2--0.1727 °2
S-0.011 Å °-0.015 Å °-0.0072 Å °-0.0249 Å °0.0048 Å °-0.003 Å °0.0125 Å °-0.0054 Å °0.0021 Å °
Refinement TLS groupSelection details: all

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