4mr6: Difference between revisions
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==Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)== | ==Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)== | ||
<StructureSection load='4mr6' size='340' side='right' caption='[[4mr6]], [[Resolution|resolution]] 1.67Å' scene=''> | <StructureSection load='4mr6' size='340' side='right'caption='[[4mr6]], [[Resolution|resolution]] 1.67Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4mr6]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4mr6]] is a 1 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=4MR6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MR6 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1K0:2-[4-(2-HYDROXYETHOXY)-3,5-DIMETHYLPHENYL]-5,7-DIMETHOXYQUINAZOLIN-4(3H)-ONE'>1K0</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1K0:2-[4-(2-HYDROXYETHOXY)-3,5-DIMETHYLPHENYL]-5,7-DIMETHOXYQUINAZOLIN-4(3H)-ONE'>1K0</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=4mr6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mr6 OCA], [https://pdbe.org/4mr6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mr6 RCSB], [https://www.ebi.ac.uk/pdbsum/4mr6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mr6 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/BRD2_HUMAN BRD2_HUMAN] May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.<ref>PMID:18406326</ref> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 21: | Line 20: | ||
==See Also== | ==See Also== | ||
*[[Bromodomain-containing protein|Bromodomain-containing protein]] | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Fedorov | [[Category: Fedorov O]] | ||
[[Category: Felletar | [[Category: Felletar I]] | ||
[[Category: Filippakopoulos | [[Category: Filippakopoulos P]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Martin | [[Category: Martin S]] | ||
[[Category: Picaud | [[Category: Picaud S]] | ||
[[Category: Weigelt J]] | |||
[[Category: Weigelt | [[Category: Von Delft F]] | ||
[[Category: | |||
Revision as of 13:03, 28 December 2022
Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)Crystal Structure of the second bromodomain of human BRD2 in complex with a quinazolinone ligand (RVX-208)
Structural highlights
FunctionBRD2_HUMAN May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1] Publication Abstract from PubMedBromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.,Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M, Bountra C, Lingard H, Fedorov O, Muller S, Brennan PE, Knapp S, Filippakopoulos P Proc Natl Acad Sci U S A. 2013 Nov 18. PMID:24248379[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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