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

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Basic information

Entry
Database: PDB / ID: 6uwu
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / Bromodomain / Inhibitor / Complex / GENE REGULATION
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 II / Brdt, bromodomain, repeat I / 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 II / Brdt, bromodomain, repeat I / 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-QKP / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsLeonard, P.G. / Joseph, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Crohns and Colitis Foundation576144 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffold Hopping, Optimization, and Pharmacological Evaluation.
Authors: Liu, Z. / Chen, H. / Wang, P. / Li, Y. / Wold, E.A. / Leonard, P.G. / Joseph, S. / Brasier, A.R. / Tian, B. / Zhou, J.
History
DepositionNov 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 10, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 11, 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)15,8927
Polymers15,0991
Non-polymers7936
Water2,846158
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein elutes from gel filtration column as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.004, 44.464, 78.177
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BRD4, HUNK1 / Plasmid: pNIC28-Bsa4 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O60885
#2: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-QKP / 2-{4-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-3,5-dimethylphenyl}-5,7-dimethoxy-4H-1-benzopyran-4-one


Mass: 482.569 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C27H34N2O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 158 / 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: 2.13 Å3/Da / Density % sol: 42.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100 mM sodium sulfate, 10% (v/v) ethylene glycol and 18% (w/v) PEG 3350
Temp details: Room temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: RIGAKU MICROMAX-003 / Wavelength: 1.54056 Å
DetectorType: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Sep 19, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54056 Å / Relative weight: 1
ReflectionResolution: 2→29.36 Å / Num. obs: 9168 / % possible obs: 99.5 % / Redundancy: 7.5 % / CC1/2: 0.99 / Rmerge(I) obs: 0.227 / Rpim(I) all: 0.087 / Rrim(I) all: 0.244 / Net I/σ(I): 7.3 / Num. measured all: 69178 / Scaling rejects: 23
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2-2.056.10.85937566140.6490.3650.9392.193.5
8.94-29.365.10.0516531270.9970.0250.05715.697.5

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.76 Å29.36 Å
Translation4.76 Å29.36 Å

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Processing

Software
NameVersionClassification
PHENIX1.16-3549-000refinement
Aimless0.7.4data scaling
PHASER2.8.3phasing
PDB_EXTRACT3.25data extraction
CrysalisPro171.39.46data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6U0D

6u0d


Resolution: 2→29.357 Å / SU ML: 0.23 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 23.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2606 912 9.99 %
Rwork0.1804 8217 -
obs0.1882 9129 99.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 70.36 Å2 / Biso mean: 16.894 Å2 / Biso min: 5.96 Å2
Refinement stepCycle: final / Resolution: 2→29.357 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1056 0 55 158 1269
Biso mean--27.28 22.68 -
Num. residues----126
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.0001-2.10550.27151210.2072110396
2.1055-2.23730.29861290.19561162100
2.2373-2.410.35431280.20431153100
2.41-2.65240.3021300.20531169100
2.6524-3.03590.26431310.19561173100
3.0359-3.82360.22881320.15751187100
3.8236-29.3570.21631410.15611270100

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