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- PDB-6cj2: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6cj2
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor JWG056
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
Chem-X27 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 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 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Sep 16, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._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
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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,2992
Polymers14,8111
Non-polymers4881
Water3,945219
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)32.816, 47.412, 78.666
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: 14811.059 Da / Num. of mol.: 1 / Fragment: residues 42-166
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-X27 / 2-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-methyl-11-(propan-2-yl)-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 487.597 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H33N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 219 / 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: 2.07 Å3/Da / Density % sol: 40.46 %
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: 0.9792 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 20, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.47→78.67 Å / Num. obs: 21521 / % possible obs: 99.7 % / Redundancy: 5.6 % / CC1/2: 0.998 / Rmerge(I) obs: 0.083 / Rpim(I) all: 0.039 / Rrim(I) all: 0.092 / Net I/σ(I): 14.1
Reflection shellResolution: 1.47→1.5 Å / Redundancy: 4.3 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 1029 / CC1/2: 0.491 / Rpim(I) all: 0.774 / % possible all: 98.8

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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: 1.47→30.286 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 24.01
RfactorNum. reflection% reflection
Rfree0.2137 1035 5.15 %
Rwork0.1827 --
obs0.1842 20080 93.04 %
Solvent computationShrinkage radii: 0.61 Å / VDW probe radii: 0.9 Å / Bsol: 51.233 Å2 / ksol: 0.393 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-9.3846 Å2-0 Å2-0 Å2
2---5.487 Å20 Å2
3----3.8977 Å2
Refinement stepCycle: LAST / Resolution: 1.47→30.286 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1025 0 36 219 1280
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061095
X-RAY DIFFRACTIONf_angle_d1.2211498
X-RAY DIFFRACTIONf_dihedral_angle_d11.463415
X-RAY DIFFRACTIONf_chiral_restr0.071159
X-RAY DIFFRACTIONf_plane_restr0.006192
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4701-1.54760.44181460.35972319X-RAY DIFFRACTION81
1.5476-1.64450.33271500.28712476X-RAY DIFFRACTION86
1.6445-1.77150.26691300.24052615X-RAY DIFFRACTION91
1.7715-1.94970.25761400.19442761X-RAY DIFFRACTION95
1.9497-2.23180.20351540.17322869X-RAY DIFFRACTION98
2.2318-2.81150.19731610.16132931X-RAY DIFFRACTION99
2.8115-30.29280.16161540.15353074X-RAY DIFFRACTION99
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)
10.66750.255-0.39170.4037-0.29591.02490.2167-0.06670.0496-0.0214-0.04260.0447-0.02730.0952-0.01950.1573-0.00010.04440.135-0.00110.1131-11.6098.115915.8761
20.7701-0.0353-0.51490.7214-0.32280.692-0.03330.0769-0.02490.1436-0.12720.11340.10130.02450.02560.1253-0.00420.0140.12750.00230.1105-10.6158-8.79925.7613
30.37280.0784-0.47410.8775-0.4010.8269-0.09360.0179-0.0952-0.08810.0388-0.21870.19570.01360.05750.1080.020200.1473-0.01410.152-2.3683-12.0539.9981
41.2577-0.6707-0.30030.74190.39580.70140.0773-0.07490.1378-0.1016-0.0097-0.1566-0.09890.0958-0.04530.1309-0.00840.02240.1236-0.00270.1473-10.41146.48774.4182
50.8409-0.0129-0.19410.7425-0.52180.7444-0.00760.07290.0262-0.116-0.0371-0.1279-0.17110.1482-0.00630.1181-0.00470.01190.1537-0.01310.1226-5.1105-3.581214.6776
60.75570.0535-0.31790.4571-0.22910.3631-0.06820.04920.0760.0690.09390.07910.08040.1286-0.00670.13060.00070.01120.15340.0080.0877-10.3167-9.409121.3405
70.571-0.74770.21731.1536-0.94581.28060.10.00350.0001-0.1612-0.04340.0310.08780.074-0.03240.1048-0.0055-00.1137-0.01930.1059-15.1838-4.44466.6832
80.04930.0524-0.1111.0197-0.49350.512-0.04310.0824-0.0335-0.09640.034-0.1067-0.0146-0.047-0.00430.1187-0.00590.01210.1409-0.01640.1177-11.062-5.7245-2.8844
93.1627-0.39971.3230.0673-0.33894.03250.1732-0.0716-0.806-0.0484-0.1130.21130.67820.0585-0.0960.26280.03750.01980.13370.04820.2507-8.1939-22.77259.2544
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 42:51)
2X-RAY DIFFRACTION2chain 'A' and (resseq 52:60)
3X-RAY DIFFRACTION3chain 'A' and (resseq 61:76)
4X-RAY DIFFRACTION4chain 'A' and (resseq 77:106)
5X-RAY DIFFRACTION5chain 'A' and (resseq 107:115)
6X-RAY DIFFRACTION6chain 'A' and (resseq 116:121)
7X-RAY DIFFRACTION7chain 'A' and (resseq 122:139)
8X-RAY DIFFRACTION8chain 'A' and (resseq 140:161)
9X-RAY DIFFRACTION9chain 'A' and (resseq 162:166)

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