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- PDB-6g0r: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6g0r
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated POLR2A peptide (K775ac/K778ac)
Components
  • Bromodomain-containing protein 4
  • DNA-directed RNA polymerase II subunit RPB1
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


microfibril binding / Abortive elongation of HIV-1 transcript in the absence of Tat / MicroRNA (miRNA) biogenesis / FGFR2 alternative splicing / Viral Messenger RNA Synthesis / Signaling by FGFR2 IIIa TM / RNA Pol II CTD phosphorylation and interaction with CE during HIV infection / RNA Pol II CTD phosphorylation and interaction with CE / Formation of the Early Elongation Complex / Formation of the HIV-1 Early Elongation Complex ...microfibril binding / Abortive elongation of HIV-1 transcript in the absence of Tat / MicroRNA (miRNA) biogenesis / FGFR2 alternative splicing / Viral Messenger RNA Synthesis / Signaling by FGFR2 IIIa TM / RNA Pol II CTD phosphorylation and interaction with CE during HIV infection / RNA Pol II CTD phosphorylation and interaction with CE / Formation of the Early Elongation Complex / Formation of the HIV-1 Early Elongation Complex / mRNA Capping / PIWI-interacting RNA (piRNA) biogenesis / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / mRNA Splicing - Minor Pathway / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RNA polymerase II C-terminal domain binding / Processing of Capped Intron-Containing Pre-mRNA / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of DNA damage checkpoint / RNA polymerase II transcribes snRNA genes / P-TEFb complex binding / negative regulation by host of viral transcription / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / RNA polymerase II, core complex / positive regulation of T-helper 17 cell lineage commitment / RNA Polymerase II Transcription Elongation / RNA polymerase II activity / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / Inhibition of DNA recombination at telomere / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / mRNA Splicing - Major Pathway / positive regulation of RNA splicing / condensed nuclear chromosome / promoter-specific chromatin binding / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of transcription elongation by RNA polymerase II / DNA-templated transcription termination / Transcriptional regulation by small RNAs / transcription coregulator activity / lysine-acetylated histone binding / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / kinase binding / DNA-directed 5'-3' RNA polymerase activity / DNA-directed RNA polymerase / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / p53 binding / chromosome / Hydrolases; Acting on ester bonds; Exoribonucleases producing 5'-phosphomonoesters / regulation of inflammatory response / positive regulation of canonical NF-kappaB signal transduction / Estrogen-dependent gene expression / transcription by RNA polymerase II / Potential therapeutics for SARS / transcription coactivator activity / hydrolase activity / transcription cis-regulatory region binding / chromatin remodeling / RNA-directed RNA polymerase / RNA-dependent RNA polymerase activity / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / magnesium ion binding / positive regulation of transcription by RNA polymerase II / DNA binding / RNA binding / zinc ion binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
RNA polymerase II, heptapeptide repeat, eukaryotic / RNA polymerase Rpb1, domain 6 / RNA polymerase Rpb1, domain 6 / RNA polymerase Rpb1 C-terminal repeat / Eukaryotic RNA polymerase II heptapeptide repeat. / RNA polymerase Rpb1, domain 7 / RNA polymerase Rpb1, domain 7 superfamily / RNA polymerase Rpb1, domain 7 / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 ...RNA polymerase II, heptapeptide repeat, eukaryotic / RNA polymerase Rpb1, domain 6 / RNA polymerase Rpb1, domain 6 / RNA polymerase Rpb1 C-terminal repeat / Eukaryotic RNA polymerase II heptapeptide repeat. / RNA polymerase Rpb1, domain 7 / RNA polymerase Rpb1, domain 7 superfamily / RNA polymerase Rpb1, domain 7 / 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 / RNA polymerase Rpb1, domain 3 superfamily / RNA polymerase Rpb1, clamp domain superfamily / DNA-directed RNA polymerase, subunit beta-prime / RNA polymerase Rpb1, domain 3 / RNA polymerase Rpb1, domain 3 / RNA polymerase Rpb1, domain 1 / RNA polymerase Rpb1, domain 1 / RNA polymerase, alpha subunit / RNA polymerase Rpb1, domain 4 / RNA polymerase Rpb1, domain 2 / RNA polymerase Rpb1, domain 4 / RNA polymerase, N-terminal / RNA polymerase Rpb1, funnel domain superfamily / RNA polymerase I subunit A N-terminus / RNA polymerase Rpb1, domain 5 / RNA polymerase Rpb1, domain 5 / 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
Bromodomain-containing protein 4 / DNA-directed RNA polymerase II subunit RPB1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.25 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: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R ...Authors: Jean-Philippe Lambert / Sarah Picaud / Takao Fujisawa / Huayun Hou / Pavel Savitsky / Liis Uusküla-Reimand / Gagan D Gupta / Hala Abdouni / Zhen-Yuan Lin / Monika Tucholska / James D R Knight / Beatriz Gonzalez-Badillo / Nicole St-Denis / Joseph A Newman / Manuel Stucki / Laurence Pelletier / Nuno Bandeira / Michael D Wilson / Panagis Filippakopoulos / Anne-Claude Gingras /
Abstract: Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, ...Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.
History
DepositionMar 19, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 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 1.2Feb 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 1.3Jan 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

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
C: DNA-directed RNA polymerase II subunit RPB1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,3833
Polymers16,3212
Non-polymers621
Water2,612145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1290 Å2
ΔGint-7 kcal/mol
Surface area7530 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.188, 52.480, 58.520
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
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 DNA-directed RNA polymerase II subunit RPB1 / RNA polymerase II subunit B1 / DNA-directed RNA polymerase II subunit A / DNA-directed RNA ...RNA polymerase II subunit B1 / DNA-directed RNA polymerase II subunit A / DNA-directed RNA polymerase III largest subunit / RNA-directed RNA polymerase II subunit RPB1


Mass: 1221.362 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: POLR2A peptide acetylated at K775 and K778 C-terminal TYR added for UV detection
Source: (synth.) Homo sapiens (human)
References: UniProt: P24928, DNA-directed RNA polymerase, RNA-directed RNA polymerase
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / 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: 2.08 Å3/Da / Density % sol: 40.81 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 20.0 % PEG 6K 10.0 % EtGly 0.1 M HEPES pH 7.0 0.1 M MgCl2

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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-F / Detector: PIXEL / Date: May 14, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9686 Å / Relative weight: 1
ReflectionResolution: 1.25→58.52 Å / Num. obs: 37495 / % possible obs: 99.9 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.142 / Rpim(I) all: 0.068 / Rrim(I) all: 0.158 / Rsym value: 0.142 / Net I/av σ(I): 1.8 / Net I/σ(I): 7.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.25-1.324.20.3232.153620.1730.3680.32399.5
1.32-1.45.30.2892.351150.1360.320.28999.9
1.4-1.495.30.2272.848280.1070.2520.227100
1.49-1.615.30.1813.444820.0850.2010.181100
1.61-1.775.10.1563.841440.0750.1740.15699.9
1.77-1.985.20.1413.937720.0670.1570.141100
1.98-2.285.50.137433650.0630.1510.13799.9
2.28-2.85.50.1373.828510.0640.1520.13799.9
2.8-3.955.30.1353.622460.0650.150.13599.9
3.95-58.524.70.1363.913300.0680.1530.13699.8

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.3 Å39.07 Å
Translation1.3 Å39.07 Å

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASER2.5.7phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Ensemble of 2OSS, 2OUO, 2GRC, 2OO1, 3DAI, 3D7C, 3DWY

2oss

2ouo

2grc

2oo1

3dai

3d7c

3dwy


Resolution: 1.25→39.07 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.971 / SU B: 1.353 / SU ML: 0.027 / SU R Cruickshank DPI: 0.0436 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.044 / ESU R Free: 0.042
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1749 1860 5 %RANDOM
Rwork0.1497 ---
obs0.1509 35571 99.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 57.34 Å2 / Biso mean: 16.758 Å2 / Biso min: 7.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å2-0 Å20 Å2
2--0.74 Å2-0 Å2
3----0.36 Å2
Refinement stepCycle: final / Resolution: 1.25→39.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1105 0 4 145 1254
Biso mean--16.69 27.57 -
Num. residues----135
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.021150
X-RAY DIFFRACTIONr_bond_other_d0.0020.021109
X-RAY DIFFRACTIONr_angle_refined_deg1.6751.9891562
X-RAY DIFFRACTIONr_angle_other_deg0.99432562
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3735133
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.76625.84953
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.09215197
X-RAY DIFFRACTIONr_dihedral_angle_4_deg26.693153
X-RAY DIFFRACTIONr_chiral_restr0.1070.2170
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211277
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02252
X-RAY DIFFRACTIONr_rigid_bond_restr3.84832259
X-RAY DIFFRACTIONr_sphericity_free21.941546
X-RAY DIFFRACTIONr_sphericity_bonded7.98852330
LS refinement shellResolution: 1.25→1.282 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.279 141 -
Rwork0.218 2571 -
all-2712 -
obs--99.05 %

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