4mr3: Difference between revisions
New page: '''Unreleased structure''' The entry 4mr3 is ON HOLD Authors: Filippakopoulos, P., Picaud, S., Felletar, I., Martin, S., Fedorov, O., von Delft, F., Arrowsmith, C.H., Edwards, A.M., Wei... |
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==Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-OH)== | |||
<StructureSection load='4mr3' size='340' side='right'caption='[[4mr3]], [[Resolution|resolution]] 1.68Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mr3]] 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=4MR3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MR3 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.68Å</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=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=4mr3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mr3 OCA], [https://pdbe.org/4mr3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mr3 RCSB], [https://www.ebi.ac.uk/pdbsum/4mr3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mr3 ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[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 == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
Bromodomains 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<ref>PMID:24248379</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4mr3" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Arrowsmith CH]] | |||
[[Category: Bountra C]] | |||
[[Category: Edwards AM]] | |||
[[Category: Fedorov O]] | |||
[[Category: Felletar I]] | |||
[[Category: Filippakopoulos P]] | |||
[[Category: Knapp S]] | |||
[[Category: Martin S]] | |||
[[Category: Picaud S]] | |||
[[Category: Weigelt J]] | |||
[[Category: Von Delft F]] | |||
Latest revision as of 19:40, 20 September 2023
Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-OH)Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-OH)
Structural highlights
DiseaseBRD4_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] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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