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- PDB-5f61: Crystal structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5f61
TitleCrystal structure of the first bromodomain of human BRD4 in complex with MA4-022-1
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION/TRANSCRIPTION INHIBITOR / ROMODOMAIN / 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-5W0 / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 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
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,81313
Polymers30,1992
Non-polymers1,61411
Water4,828268
1
A: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,7514
Polymers15,0991
Non-polymers6523
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Bromodomain-containing protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,0629
Polymers15,0991
Non-polymers9628
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)34.850, 78.510, 47.090
Angle α, β, γ (deg.)90.00, 91.74, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 15099.380 Da / Num. of mol.: 2 / 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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-5W0 / ~{N}-[3-[[2-[[3-fluoranyl-4-(4-methylpiperazin-1-yl)phenyl]amino]-5-methyl-pyrimidin-4-yl]amino]phenyl]-2-methyl-propane-2-sulfonamide


Mass: 527.657 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H34FN7O2S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 268 / 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: 2.13 Å3/Da / Density % sol: 42.31 %
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 MA4-022-1
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: Jun 24, 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: 1.45→39.255 Å / Num. obs: 43128 / % possible obs: 96.2 % / Observed criterion σ(I): -3 / Redundancy: 7.36 % / Biso Wilson estimate: 10.48 Å2 / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.059 / Rrim(I) all: 0.063 / Rsym value: 0.059 / Χ2: 0.97 / Net I/σ(I): 25 / Num. measured all: 317302
Reflection shellResolution: 1.45→1.49 Å / Redundancy: 2.95 % / Rmerge F obs: 0.999 / Rmerge(I) obs: 0.036 / Mean I/σ(I) obs: 5 / Num. measured obs: 3759 / Num. possible: 524 / Num. unique obs: 516 / Rrim(I) all: 0.039 / Rsym value: 0.2 / Rejects: 0 / % possible all: 93.2

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Processing

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

4o78


Resolution: 1.45→39.255 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 15.86 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1641 1294 3 %Random selection
Rwork0.1274 ---
obs-43123 96.18 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.45→39.255 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2124 0 110 268 2502
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092333
X-RAY DIFFRACTIONf_angle_d1.3183174
X-RAY DIFFRACTIONf_dihedral_angle_d17.48905
X-RAY DIFFRACTIONf_chiral_restr0.064324
X-RAY DIFFRACTIONf_plane_restr0.006403
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.45-1.5080.17611390.12584495X-RAY DIFFRACTION93
1.508-1.57670.17821400.10964536X-RAY DIFFRACTION94
1.5767-1.65980.13741420.10714600X-RAY DIFFRACTION95
1.6598-1.76380.17151420.11184587X-RAY DIFFRACTION96
1.7638-1.89990.16151430.11784626X-RAY DIFFRACTION96
1.8999-2.09110.15921450.12124668X-RAY DIFFRACTION97
2.0911-2.39370.16461450.12664710X-RAY DIFFRACTION97
2.3937-3.01560.16631470.13934754X-RAY DIFFRACTION98
3.0156-39.26940.16481510.13634853X-RAY DIFFRACTION99

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