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Yorodumi- PDB-6g0q: Crystal Structure of the first bromodomain of human BRD4 in compl... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6g0q | ||||||
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Title | Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated GATA1 peptide (K312ac/K315ac) | ||||||
Components |
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Keywords | TRANSCRIPTION / Bromodomain / complex | ||||||
Function / homology | Function and homology information : / regulation of primitive erythrocyte differentiation / basophil differentiation / eosinophil fate commitment / regulation of definitive erythrocyte differentiation / RNA polymerase II-specific DNA-binding transcription factor binding => GO:0061629 / eosinophil differentiation / regulation of glycoprotein biosynthetic process / megakaryocyte differentiation / negative regulation of transcription regulatory region DNA binding ...: / regulation of primitive erythrocyte differentiation / basophil differentiation / eosinophil fate commitment / regulation of definitive erythrocyte differentiation / RNA polymerase II-specific DNA-binding transcription factor binding => GO:0061629 / eosinophil differentiation / regulation of glycoprotein biosynthetic process / megakaryocyte differentiation / negative regulation of transcription regulatory region DNA binding / dendritic cell differentiation / chromatin => GO:0000785 / regulation of megakaryocyte differentiation / negative regulation of bone mineralization / C2H2 zinc finger domain binding / cellular response to thyroid hormone stimulus / regulation of hematopoietic stem cell differentiation / embryonic hemopoiesis / platelet formation / erythrocyte development / positive regulation of osteoblast proliferation / RNA polymerase II C-terminal domain binding / negative regulation of DNA damage checkpoint / P-TEFb complex binding / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation by host of viral transcription / cell fate commitment / positive regulation of T-helper 17 cell lineage commitment / homeostasis of number of cells within a tissue / positive regulation of G2/M transition of mitotic cell cycle / transcription repressor complex / histone reader activity / RNA polymerase II CTD heptapeptide repeat kinase activity / erythrocyte differentiation / positive regulation of erythrocyte differentiation / condensed nuclear chromosome / protein-DNA complex / positive regulation of transcription elongation by RNA polymerase II / transcription coregulator activity / RNA polymerase II transcription regulatory region sequence-specific DNA binding / lysine-acetylated histone binding / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / chromatin DNA binding / platelet aggregation / male gonad development / positive regulation of peptidyl-tyrosine phosphorylation / blood coagulation / sequence-specific double-stranded DNA binding / p53 binding / cell-cell signaling / RUNX1 regulates transcription of genes involved in differentiation of HSCs / chromosome / Factors involved in megakaryocyte development and platelet production / regulation of inflammatory response / DNA-binding transcription activator activity, RNA polymerase II-specific / positive regulation of canonical NF-kappaB signal transduction / in utero embryonic development / transcription regulator complex / Potential therapeutics for SARS / sequence-specific DNA binding / transcription coactivator activity / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / chromatin remodeling / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of cell population proliferation / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / enzyme binding / positive regulation of transcription by RNA polymerase II / DNA binding / zinc ion binding / nucleoplasm / nucleus Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.4 Å | ||||||
Authors | Filippakopoulos, P. / Picaud, S. / Newman, J. / Sorrell, F. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. | ||||||
Funding support | United Kingdom, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 6g0q.cif.gz | 81.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6g0q.ent.gz | 58.8 KB | Display | PDB format |
PDBx/mmJSON format | 6g0q.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/g0/6g0q ftp://data.pdbj.org/pub/pdb/validation_reports/g0/6g0q | HTTPS FTP |
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-Related structure data
Related structure data | 5nncC 5nndC 5nneC 5nnfC 5nngC 6g0oC 6g0pC 6g0rC 6g0sC 2grcS 2oo1S 2ossS 2ouoS 3d7cS 3daiS 3dwyS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
#1: Protein | 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 |
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#2: Protein/peptide | Mass: 1266.471 Da / Num. of mol.: 1 / Source method: obtained synthetically Details: GATA1 peptide acetylated at K312 and K315 C-terminal TYR added for UV detection Source: (synth.) Homo sapiens (human) / References: UniProt: P15976 |
#3: Chemical | ChemComp-EDO / |
#4: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.21 Å3/Da / Density % sol: 44.24 % |
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Crystal grow | Temperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 30.0% PEG 1k 0.1M SPG pH 8.0 |
-Data collection
Diffraction | Mean temperature: 100 K | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Apr 16, 2016 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 0.9795 Å / Relative weight: 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 1.4→43.855 Å / Num. all: 28201 / Num. obs: 28201 / % possible obs: 98.4 % / Redundancy: 6.4 % / Rpim(I) all: 0.03 / Rrim(I) all: 0.078 / Rsym value: 0.071 / Net I/av σ(I): 5.7 / Net I/σ(I): 24.4 / Num. measured all: 179422 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Phasing
Phasing | Method: molecular replacement | |||||||||
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Phasing MR | Model details: Phaser MODE: MR_AUTO
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: Ensemble of 2OSS, 2OUO, 2GRC, 2OO1, 3DAI, 3D7C, 3DWY Resolution: 1.4→41.17 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.923 / SU B: 1.231 / SU ML: 0.023 / SU R Cruickshank DPI: 0.0625 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.063 / ESU R Free: 0.058 Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 75.43 Å2 / Biso mean: 9.027 Å2 / Biso min: 2.14 Å2
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Refinement step | Cycle: final / Resolution: 1.4→41.17 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.4→1.436 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
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