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- PDB-4xy9: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 4xy9
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a 2-amine-9H-purine ligand
ComponentsBromodomain-containing protein 4
KeywordsTRANSCRIPTION / Bromodomain / complex / ligand / Structural Genomics Consortium / SGC
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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase 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 / chromatin / 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 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / NET domain / Bromodomain extra-terminal - transcription regulation / Bromodomain-like / Histone Acetyltransferase; Chain A ...Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily / NET domain profile. / Brdt, bromodomain, repeat II / Brdt, bromodomain, repeat I / 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
6-(5-bromo-2-methoxyphenyl)-9H-purin-2-amine / Bromodomain-containing protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.83 Å
AuthorsPicaud, S. / von Delft, F. / Edwards, A.M. / Arrowsmith, C.H. / Bountra, C. / Filippakopoulos, P. / Structural Genomics Consortium (SGC)
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: J.Med.Chem. / Year: 2015
Title: 9H-Purine Scaffold Reveals Induced-Fit Pocket Plasticity of the BRD9 Bromodomain.
Authors: Picaud, S. / Strocchia, M. / Terracciano, S. / Lauro, G. / Mendez, J. / Daniels, D.L. / Riccio, R. / Bifulco, G. / Bruno, I. / Filippakopoulos, P.
History
DepositionFeb 2, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Mar 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 18, 2015Group: Database references
Revision 1.2Apr 8, 2015Group: Database references
Revision 1.3May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)15,4823
Polymers15,0991
Non-polymers3822
Water2,180121
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint3 kcal/mol
Surface area7300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.915, 44.229, 79.584
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 / BRD4


Mass: 15099.380 Da / Num. of mol.: 1 / Fragment: UNP residues 42-168
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) / Variant (production host): R3 / References: UniProt: O60885
#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-43U / 6-(5-bromo-2-methoxyphenyl)-9H-purin-2-amine


Mass: 320.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H10BrN5O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 121 / 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: 2.15 Å3/Da / Density % sol: 42.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 0.20M NaNO3, 20.0% PEG 3350, 10.0% EtGly

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5 Å
DetectorType: APEX II CCD / Detector: CCD / Date: Nov 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5 Å / Relative weight: 1
ReflectionResolution: 1.83→44.23 Å / Num. obs: 12065 / % possible obs: 100 % / Redundancy: 5.15 % / Rmerge(I) obs: 0.064 / Rsym value: 0.064 / Net I/σ(I): 16.98
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. possibleNum. unique obsNet I/σ(I) obs% possible all
1.83-1.873.610.2022.295795782.0999.8
1.87-1.913.740.1986666652.2499.8
1.91-1.953.830.176516512.59100
1.95-23.90.147227213.4599.9
2-2.054.080.1296586583.97100
2.05-2.14.110.1086086074.9699.8
2.1-2.164.320.1016406405.88100
2.16-2.234.360.096736736.96100
2.23-2.314.680.0866696697.85100
2.31-2.44.760.0836546548.5100
2.4-2.55.010.0726166169.93100
2.5-2.625.240.06962962911.25100
2.62-2.765.510.0660560514.19100
2.76-2.955.840.05564364317.48100
2.95-3.196.420.05362162123.24100
3.19-3.537.250.06460760733.35100
3.53-4.077.350.05261061051.53100
4.07-5.227.360.05261361359.72100
5.22-44.237.020.06560660561.799.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å39.79 Å
Translation3.5 Å39.79 Å

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Processing

Software
NameVersionClassification
PROTEUM PLUSdata reduction
PROTEUM PLUSdata scaling
PHASER2.5.6phasing
REFMAC5.8.0073refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.83→39.79 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.1734 / WRfactor Rwork: 0.141 / FOM work R set: 0.8542 / SU B: 5.319 / SU ML: 0.086 / SU R Cruickshank DPI: 0.1241 / SU Rfree: 0.1241 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.124 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2061 601 5 %RANDOM
Rwork0.1572 11421 --
obs0.1598 11421 99.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 75.17 Å2 / Biso mean: 18.723 Å2 / Biso min: 6.62 Å2
Baniso -1