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==Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated POLR2A peptide (K775ac/K778ac)==
==Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated POLR2A peptide (K775ac/K778ac)==
<StructureSection load='6g0r' size='340' side='right' caption='[[6g0r]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
<StructureSection load='6g0r' size='340' side='right'caption='[[6g0r]], [[Resolution|resolution]] 1.25&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6g0r]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G0R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6G0R FirstGlance]. <br>
<table><tr><td colspan='2'>[[6g0r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6G0R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6G0R FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.25&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALY:N(6)-ACETYLLYSINE'>ALY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6g0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g0r OCA], [https://pdbe.org/6g0r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6g0r RCSB], [https://www.ebi.ac.uk/pdbsum/6g0r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6g0r ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6g0r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6g0r OCA], [http://pdbe.org/6g0r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6g0r RCSB], [http://www.ebi.ac.uk/pdbsum/6g0r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6g0r ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>
[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.<ref>PMID:12543779</ref> <ref>PMID:11733348</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). [[http://www.uniprot.org/uniprot/RPB1_HUMAN RPB1_HUMAN]] DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Forms the polymerase active center together with the second largest subunit. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB1 is part of the core element with the central large cleft, the clamp element that moves to open and close the cleft and the jaws that are thought to grab the incoming DNA template. At the start of transcription, a single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol II. A bridging helix emanates from RPB1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol II by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition. During transcription elongation, Pol II moves on the template as the transcript elongates. Elongation is influenced by the phosphorylation status of the C-terminal domain (CTD) of Pol II largest subunit (RPB1), which serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. Acts as a RNA-dependent RNA polymerase when associated with small delta antigen of Hepatitis delta virus, acting both as a replicate and transcriptase for the viral RNA circular genome.<ref>PMID:9852112</ref> <ref>PMID:18032511</ref> 
[https://www.uniprot.org/uniprot/BRD4_HUMAN BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Arrowsmith, C H]]
[[Category: Large Structures]]
[[Category: Bountra, C]]
[[Category: Arrowsmith CH]]
[[Category: Delft, F von]]
[[Category: Bountra C]]
[[Category: Edwards, A M]]
[[Category: Edwards AM]]
[[Category: Filippakopoulos, P]]
[[Category: Filippakopoulos P]]
[[Category: Picaud, S]]
[[Category: Picaud S]]
[[Category: Pike, A C.W]]
[[Category: Pike ACW]]
[[Category: Bromodomain]]
[[Category: Von Delft F]]
[[Category: Complex]]
[[Category: Transcription]]

Latest revision as of 08:14, 21 November 2024

Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated POLR2A peptide (K775ac/K778ac)Crystal Structure of the first bromodomain of human BRD4 in complex with an acetylated POLR2A peptide (K775ac/K778ac)

Structural highlights

6g0r is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.25Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2]

Function

BRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).

Publication Abstract from PubMed

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.

Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.,Lambert JP, Picaud S, Fujisawa T, Hou H, Savitsky P, Uuskula-Reimand L, Gupta GD, Abdouni H, Lin ZY, Tucholska M, Knight JDR, Gonzalez-Badillo B, St-Denis N, Newman JA, Stucki M, Pelletier L, Bandeira N, Wilson MD, Filippakopoulos P, Gingras AC Mol Cell. 2018 Dec 13. pii: S1097-2765(18)30948-1. doi:, 10.1016/j.molcel.2018.11.006. PMID:30554943[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003 Jan 15;63(2):304-7. PMID:12543779
  2. ↑ French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001 Dec;159(6):1987-92. PMID:11733348 doi:10.1016/S0002-9440(10)63049-0
  3. ↑ Lambert JP, Picaud S, Fujisawa T, Hou H, Savitsky P, Uuskula-Reimand L, Gupta GD, Abdouni H, Lin ZY, Tucholska M, Knight JDR, Gonzalez-Badillo B, St-Denis N, Newman JA, Stucki M, Pelletier L, Bandeira N, Wilson MD, Filippakopoulos P, Gingras AC. Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Mol Cell. 2018 Dec 13. pii: S1097-2765(18)30948-1. doi:, 10.1016/j.molcel.2018.11.006. PMID:30554943 doi:http://dx.doi.org/10.1016/j.molcel.2018.11.006

6g0r, resolution 1.25Å

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