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- PDB-5nnc: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 5nnc
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with a diacetylated histone 4 peptide (H3K9ac/K14ac)
Components
  • Bromodomain-containing protein 4BRD4
  • Histone H3
KeywordsTRANSCRIPTION / Bromodomain / complex
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 / Chromatin modifying enzymes / epigenetic regulation of gene expression / positive regulation of G2/M transition of mitotic cell cycle / telomere organization / histone reader activity / RNA Polymerase I Promoter Opening ...RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation by host of viral transcription / Chromatin modifying enzymes / epigenetic regulation of gene expression / positive regulation of G2/M transition of mitotic cell cycle / telomere organization / histone reader activity / RNA Polymerase I Promoter Opening / Interleukin-7 signaling / Assembly of the ORC complex at the origin of replication / RNA polymerase II CTD heptapeptide repeat kinase activity / DNA methylation / Condensation of Prophase Chromosomes / HCMV Late Events / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / SIRT1 negatively regulates rRNA expression / PRC2 methylates histones and DNA / condensed nuclear chromosome / Defective pyroptosis / HDACs deacetylate histones / positive regulation of transcription elongation by RNA polymerase II / RNA Polymerase I Promoter Escape / transcription coregulator activity / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / lysine-acetylated histone binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / NoRC negatively regulates rRNA expression / B-WICH complex positively regulates rRNA expression / HDMs demethylate histones / PKMTs methylate histone lysines / RMTs methylate histone arginines / Meiotic recombination / Pre-NOTCH Transcription and Translation / nucleosome assembly / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / nucleosome / p53 binding / gene expression / chromosome / RUNX1 regulates transcription of genes involved in differentiation of HSCs / chromatin organization / Factors involved in megakaryocyte development and platelet production / HATs acetylate histones / regulation of inflammatory response / Senescence-Associated Secretory Phenotype (SASP) / positive regulation of canonical NF-kappaB signal transduction / Oxidative Stress Induced Senescence / Estrogen-dependent gene expression / Potential therapeutics for SARS / transcription coactivator activity / transcription cis-regulatory region binding / chromatin remodeling / cadherin binding / Amyloid fiber formation / protein heterodimerization activity / 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 / protein-containing complex / DNA binding / extracellular exosome / extracellular region / nucleoplasm / membrane / 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 / Histone H3 signature 1. / Histone H3 signature 2. ...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 / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Bromodomain-like / Histone Acetyltransferase; Chain A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Bromodomain, conserved site / Bromodomain signature. / Bromodomain / Bromodomain profile. / bromo domain / Bromodomain / Bromodomain-like superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / Histone H3.1 / Histone H3-7
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.22 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Pike, A.C.W. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust095751/Z/11/Z United Kingdom
CitationJournal: Mol. Cell / Year: 2019
Title: Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.
Authors: Lambert, J.P. / Picaud, S. / Fujisawa, T. / Hou, H. / Savitsky, P. / Uuskula-Reimand, L. / Gupta, G.D. / Abdouni, H. / Lin, Z.Y. / Tucholska, M. / Knight, J.D.R. / Gonzalez-Badillo, B. / St- ...Authors: Lambert, J.P. / Picaud, S. / Fujisawa, T. / Hou, H. / Savitsky, P. / Uuskula-Reimand, L. / Gupta, G.D. / Abdouni, H. / Lin, Z.Y. / Tucholska, M. / Knight, J.D.R. / Gonzalez-Badillo, B. / St-Denis, N. / Newman, J.A. / Stucki, M. / Pelletier, L. / Bandeira, N. / Wilson, M.D. / Filippakopoulos, P. / Gingras, A.C.
History
DepositionApr 8, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 28, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.2Dec 26, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Feb 20, 2019Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.4Jan 17, 2024Group: 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
B: Bromodomain-containing protein 4
C: Histone H3
D: Histone H3


Theoretical massNumber of molelcules
Total (without water)34,1854
Polymers34,1854
Non-polymers00
Water1,13563
1
A: Bromodomain-containing protein 4
C: Histone H3


Theoretical massNumber of molelcules
Total (without water)17,0932
Polymers17,0932
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area880 Å2
ΔGint-8 kcal/mol
Surface area7610 Å2
MethodPISA
2
B: Bromodomain-containing protein 4
D: Histone H3


Theoretical massNumber of molelcules
Total (without water)17,0932
Polymers17,0932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area870 Å2
ΔGint-8 kcal/mol
Surface area7570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.495, 51.947, 61.720
Angle α, β, γ (deg.)90.000, 92.310, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Bromodomain-containing protein 4 / BRD4 / 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 BL21(DE3) (bacteria) / Variant (production host): R3 / References: UniProt: O60885
#2: Protein/peptide Histone H3 /


Mass: 1993.271 Da / Num. of mol.: 2 / Fragment: UNP residues 5-21 / Source method: obtained synthetically / Details: Histone H3 peptide / Source: (synth.) Homo sapiens (human) / References: UniProt: Q5TEC6, UniProt: P68431*PLUS
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 63 / 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: 43.37 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.20M LiCl 0.1M TRIS pH 8.0 20.0% PEG 6K 10.0% EtGly

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.9686 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 2.205→19.86 Å / Num. obs: 13530 / % possible obs: 98.8 % / Redundancy: 3 % / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.042 / Rrim(I) all: 0.074 / Rsym value: 0.061 / Net I/av σ(I): 7.5 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsRpim(I) allRrim(I) allRsym value% possible all
2.205-2.3230.63510.440.7760.63598.2
2.32-2.473.10.3122.20.2090.3770.31298.3
2.47-2.6430.1993.30.1350.2420.19998.7
2.64-2.853.10.12450.0850.1510.12499
2.85-3.123.10.0847.20.0580.1020.08498.9
3.12-3.4930.0649.10.0440.0780.06499.4
3.49-4.033.10.04612.40.0320.0570.04699.2
4.03-4.9330.04214.20.0280.0510.04299.5
4.93-6.9730.04213.60.0280.0510.04299.7
6.97-19.6522.90.03512.10.0250.0430.03595.2

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å19.65 Å
Translation2.5 Å19.65 Å

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Processing

Software
NameVersionClassification
SCALA3.3.20data scaling
PHASER2.3.0phasing
REFMACrefinement
PDB_EXTRACT3.22data extraction
MOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2OSS

2oss


Resolution: 2.22→19.86 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.921 / SU B: 15.544 / SU ML: 0.194 / SU R Cruickshank DPI: 0.3207 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.321 / ESU R Free: 0.251
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES: WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2645 657 4.9 %RANDOM
Rwork0.1845 ---
obs0.1885 12650 98.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 168.51 Å2 / Biso mean: 40.28 Å2 / Biso min: 17.96 Å2
Baniso -1Baniso -2Baniso -3
1-0.21 Å20 Å2-1.9 Å2
2--0.53 Å20 Å2
3----0.89 Å2
Refinement stepCycle: final / Resolution: 2.22→19.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2144 0 0 63 2207
Biso mean---41.37 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.022217
X-RAY DIFFRACTIONr_bond_other_d0.0010.021495
X-RAY DIFFRACTIONr_angle_refined_deg1.6481.9813023
X-RAY DIFFRACTIONr_angle_other_deg0.94833683
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1295266
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.54525.6100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.4315354
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.804156
X-RAY DIFFRACTIONr_chiral_restr0.090.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0212418
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02412
LS refinement shellResolution: 2.215→2.272 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 46 -
Rwork0.362 852 -
all-898 -
obs--95.63 %
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)
11.41040.06810.84590.35270.70621.8232-0.1968-0.06670.04720.02170.10780.016-0.09750.1070.0890.1650.0071-0.01360.1299-0.00520.144625.46750.898955.8812
20.6418-0.1017-0.05430.69520.70791.81150.0824-0.0224-0.07590.05790.0191-0.11470.0321-0.0507-0.10150.1571-0.0192-0.03990.06020.01480.203835.157621.64630.3281
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A42 - 166
2X-RAY DIFFRACTION2B42 - 166

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