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- PDB-5f62: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5f62
TitleCrystal structure of the first bromodomain of human BRD4 in complex with MA4-022-2
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / BROMODOMAIN / CAP / HUNK1 / MCAP / PROTEIN BINDING-INHIBITOR COMPLEX / MITOTIC CHROMOSOME ASSOCIATED PROTEIN / CELL CYCLE / INHIBITOR / 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-5W1 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsEmber, S.W. / Zhu, J.-Y. / Schonbrunn, E.
CitationJournal: Mol. Cancer Ther. / Year: 2017
Title: Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics.
Authors: Ember, S.W. / Lambert, Q.T. / Berndt, N. / Gunawan, S. / Ayaz, M. / Tauro, M. / Zhu, J.Y. / Cranfill, P.J. / Greninger, P. / Lynch, C.C. / Benes, C.H. / Lawrence, H.R. / Reuther, G.W. / ...Authors: Ember, S.W. / Lambert, Q.T. / Berndt, N. / Gunawan, S. / Ayaz, M. / Tauro, M. / Zhu, J.Y. / Cranfill, P.J. / Greninger, P. / Lynch, C.C. / Benes, C.H. / Lawrence, H.R. / Reuther, G.W. / Lawrence, N.J. / Schonbrunn, E.
History
DepositionDec 4, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2017Group: Database references
Revision 1.2Jun 14, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_volume ..._citation.country / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Sep 27, 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)16,0348
Polymers15,0991
Non-polymers9357
Water2,774154
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)37.830, 44.210, 78.520
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 44-168
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: PNIC28-BSA4 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)-R3 / References: UniProt: O60885
#2: Chemical ChemComp-5W1 / ~{N}-[2-chloranyl-5-[[2-[[3-fluoranyl-4-(4-methylpiperazin-1-yl)phenyl]amino]-5-methyl-pyrimidin-4-yl]amino]phenyl]-2-methyl-propane-2-sulfonamide


Mass: 562.102 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33ClFN7O2S
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 154 / 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: 2.17 Å3/Da / Density % sol: 43.43 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 12.5 MG/ML BRD4, 5MM HEPES PH 7.5, 50MM SODIUM CHLORIDE, 0.5MM DTT, 50MM TRIS PH8.5, 0.1M AMMONIUM SULFATE, 12.5% PEG 3,350, 10% DMSO, 1 MM MA4-022-2
PH range: 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 27, 2015
RadiationMonochromator: ROSENBAUM-ROCK DOUBLE-CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.35→39.26 Å / Num. obs: 29629 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 7.1 % / Biso Wilson estimate: 10.5 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.047 / Rrim(I) all: 0.05 / Rsym value: 0.047 / Χ2: 0.963 / Net I/σ(I): 25.2 / Num. measured all: 211432
Reflection shellResolution: 1.35→1.39 Å / Redundancy: 7.1 % / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.029 / Mean I/σ(I) obs: 4.8 / Num. measured obs: 2434 / Num. possible: 395 / Num. unique obs: 392 / Rrim(I) all: 0.032 / Rsym value: 0.387 / Rejects: 0 / % possible all: 99.6

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4O78

4o78


Resolution: 1.35→39.26 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 16.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1829 1215 4.1 %Random selection
Rwork0.1385 28413 --
obs-29628 99.91 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 63.33 Å2 / Biso mean: 17.425 Å2 / Biso min: 6.21 Å2
Refinement stepCycle: final / Resolution: 1.35→39.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1062 0 131 154 1347
Biso mean--29.7 25.64 -
Num. residues----127
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081171
X-RAY DIFFRACTIONf_angle_d1.2321588
X-RAY DIFFRACTIONf_chiral_restr0.065160
X-RAY DIFFRACTIONf_plane_restr0.006201
X-RAY DIFFRACTIONf_dihedral_angle_d16.508463
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.3501-1.40410.18931320.142630943226
1.4041-1.4680.18091320.125630963228
1.468-1.54540.15561330.115930933226
1.5454-1.64220.17481340.11531473281
1.6422-1.7690.17061340.119131293263
1.769-1.94710.17591340.127631373271
1.9471-2.22880.15621360.127431843320
2.2288-2.80790.15871360.146931883324
2.8079-39.27660.22181440.155733453489

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