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- PDB-6g0p: Crystal Structure of the first bromodomain of human BRD4 in compl... -

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Basic information

Entry
Database: PDB / ID: 6g0p
TitleCrystal Structure of the first bromodomain of human BRD4 in complex with an acetylated E2F1 peptide (K117ac/K120ac)
Components
  • Bromodomain-containing protein 4
  • Transcription factor E2F1
KeywordsTRANSCRIPTION / Bromodomain / complex
Function / homology
Function and homology information


Rb-E2F complex / lens fiber cell apoptotic process / negative regulation of fat cell proliferation / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Transcription of E2F targets under negative control by DREAM complex / mRNA stabilization / anoikis / Activation of NOXA and translocation to mitochondria / Activation of PUMA and translocation to mitochondria ...Rb-E2F complex / lens fiber cell apoptotic process / negative regulation of fat cell proliferation / Inhibition of replication initiation of damaged DNA by RB1/E2F1 / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / Transcription of E2F targets under negative control by DREAM complex / mRNA stabilization / anoikis / Activation of NOXA and translocation to mitochondria / Activation of PUMA and translocation to mitochondria / DNA-binding transcription activator activity / G1/S-Specific Transcription / negative regulation of fat cell differentiation / G2 Phase / Transcriptional Regulation by E2F6 / negative regulation of DNA binding / regulation of G1/S transition of mitotic cell cycle / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / intrinsic apoptotic signaling pathway by p53 class mediator / P-TEFb complex binding / negative regulation by host of viral transcription / cis-regulatory region sequence-specific DNA binding / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / positive regulation of T-helper 17 cell lineage commitment / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / forebrain development / positive regulation of G2/M transition of mitotic cell cycle / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / condensed nuclear chromosome / DNA damage checkpoint signaling / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / lysine-acetylated histone binding / Oncogene Induced Senescence / Pre-NOTCH Transcription and Translation / G1/S transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / RNA polymerase II transcription regulator complex / Cyclin D associated events in G1 / intrinsic apoptotic signaling pathway in response to DNA damage / sequence-specific double-stranded DNA binding / positive regulation of fibroblast proliferation / p53 binding / cellular response to xenobiotic stimulus / chromosome / regulation of inflammatory response / Oxidative Stress Induced Senescence / DNA-binding transcription factor binding / positive regulation of canonical NF-kappaB signal transduction / sequence-specific DNA binding / Potential therapeutics for SARS / molecular adaptor activity / transcription coactivator activity / protein dimerization activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / DNA-templated transcription / centrosome / DNA damage response / chromatin binding / positive regulation of gene expression / regulation of DNA-templated transcription / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / enzyme binding / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / DNA binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
E2F transcription factor, CC-MB domain / E2F transcription factor CC-MB domain / E2F Family / E2F-DP heterodimerization region / E2F/DP family, winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / Bromodomain protein 4, C-terminal / C-terminal domain of bromodomain protein 4 / NET domain superfamily ...E2F transcription factor, CC-MB domain / E2F transcription factor CC-MB domain / E2F Family / E2F-DP heterodimerization region / E2F/DP family, winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / E2F/DP family winged-helix DNA-binding domain / 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 / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Bromodomain-containing protein 4 / Transcription factor E2F1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.3 Å
AuthorsFilippakopoulos, P. / Picaud, S. / Krojer, T. / Sorrell, F. / 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

Downloads & links

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Assembly

Deposited unit
A: Bromodomain-containing protein 4
B: Transcription factor E2F1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,0043
Polymers16,9422
Non-polymers621
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1310 Å2
ΔGint-6 kcal/mol
Surface area7770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.137, 53.358, 58.126
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 Transcription factor E2F1 / E2F-1 / PBR3 / Retinoblastoma-associated protein 1 / RBAP-1 / Retinoblastoma-binding protein 3 / ...E2F-1 / PBR3 / Retinoblastoma-associated protein 1 / RBAP-1 / Retinoblastoma-binding protein 3 / RBBP-3 / pRB-binding protein E2F-1


Mass: 1843.026 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: E2F1 peptide acetylated at K117 and K120 / Source: (synth.) Homo sapiens (human) / References: UniProt: Q01094
#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.: 174 / 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: 2.16 Å3/Da / Density % sol: 42.92 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 20.0 % PEG3350 10.0 % EtGly 0.2 M NaCHO

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Dec 13, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.3→58.126 Å / Num. all: 34488 / Num. obs: 34488 / % possible obs: 99.9 % / Redundancy: 6.7 % / Rpim(I) all: 0.014 / Rrim(I) all: 0.036 / Rsym value: 0.034 / Net I/av σ(I): 9.6 / Net I/σ(I): 29.6 / Num. measured all: 232698
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.3-1.374.90.1764.549290.0870.1970.17699.6
1.37-1.456.90.1355.747090.0550.1460.135100
1.45-1.557.10.0938.244080.0370.10.093100
1.55-1.687.20.0671141460.0270.0730.067100
1.68-1.847.10.04814.738200.0190.0510.048100
1.84-2.067.20.0361734600.0140.0390.036100
2.06-2.377.20.03119.230820.0120.0330.031100
2.37-2.917.10.0319.126350.0120.0320.03100
2.91-4.116.90.02818.520780.0110.030.028100
4.11-58.1266.50.02719.912210.0110.0290.02799.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.5 Å39.31 Å
Translation3.5 Å39.31 Å

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Processing

Software
NameVersionClassification
SCALA3.3.22data scaling
PHASER2.5.7phasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
MOSFLMdata 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: 1.3→39.31 Å / Cor.coef. Fo:Fc: 0.979 / Cor.coef. Fo:Fc free: 0.976 / SU B: 1.061 / SU ML: 0.021 / SU R Cruickshank DPI: 0.0413 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.041 / ESU R Free: 0.039
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1473 1796 5.2 %RANDOM
Rwork0.1249 ---
obs0.1261 32631 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 62.72 Å2 / Biso mean: 16.906 Å2 / Biso min: 8.27 Å2
Baniso -1Baniso -2Baniso -3
1-0.11 Å20 Å20 Å2
2--0.79 Å2-0 Å2
3----0.9 Å2
Refinement stepCycle: final / Resolution: 1.3→39.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1110 0 4 174 1288
Biso mean--17.92 27.94 -
Num. residues----135
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021161
X-RAY DIFFRACTIONr_bond_other_d0.0020.021115
X-RAY DIFFRACTIONr_angle_refined_deg1.6161.9871579
X-RAY DIFFRACTIONr_angle_other_deg0.99532586
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5025137
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.52425.92654
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.55815200
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.806153
X-RAY DIFFRACTIONr_chiral_restr0.1140.2168
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211294
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02255
X-RAY DIFFRACTIONr_rigid_bond_restr2.33232276
X-RAY DIFFRACTIONr_sphericity_free20.381552
X-RAY DIFFRACTIONr_sphericity_bonded6.63852365
LS refinement shellResolution: 1.3→1.334 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.166 126 -
Rwork0.129 2361 -
all-2487 -
obs--99.16 %

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