4mr4

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{{STRUCTURE_4mr4| PDB=4mr4 | SCENE= }}
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==Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-208)==
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===Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-208)===
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<StructureSection load='4mr4' size='340' side='right' caption='[[4mr4]], [[Resolution|resolution]] 1.66&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24248379}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4mr4]] is a 1 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=4MR4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MR4 FirstGlance]. <br>
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==Disease==
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</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=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mr3|4mr3]], [[4mr5|4mr5]], [[4mr6|4mr6]]</td></tr>
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<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>
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<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=4mr4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mr4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mr4 RCSB], [http://www.ebi.ac.uk/pdbsum/4mr4 PDBsum]</span></td></tr>
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</table>
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== 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>
[[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>
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== Function ==
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==Function==
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[[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/BRD4_HUMAN BRD4_HUMAN]] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity).
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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>
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[[4mr4]] is a 1 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=4MR4 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<ref group="xtra">PMID:024248379</ref><references group="xtra"/><references/>
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</div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Human]]
[[Category: Human]]
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[[Category: Arrowsmith, C H.]]
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[[Category: Arrowsmith, C H]]
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[[Category: Bountra, C.]]
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[[Category: Bountra, C]]
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[[Category: Delft, F von.]]
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[[Category: Delft, F von]]
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[[Category: Edwards, A M.]]
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[[Category: Edwards, A M]]
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[[Category: Fedorov, O.]]
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[[Category: Fedorov, O]]
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[[Category: Felletar, I.]]
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[[Category: Felletar, I]]
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[[Category: Filippakopoulos, P.]]
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[[Category: Filippakopoulos, P]]
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[[Category: Knapp, S.]]
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[[Category: Knapp, S]]
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[[Category: Martin, S.]]
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[[Category: Martin, S]]
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[[Category: Picaud, S.]]
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[[Category: Picaud, S]]
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[[Category: Weigelt, J.]]
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[[Category: Weigelt, J]]
[[Category: Brd]]
[[Category: Brd]]
[[Category: Brd4]]
[[Category: Brd4]]
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[[Category: Sgc]]
[[Category: Sgc]]
[[Category: Small molecule inhibitor]]
[[Category: Small molecule inhibitor]]
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[[Category: Structural genomics consortium]]
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[[Category: Structural genomic]]
[[Category: Transcription-transcription inhibitor complex]]
[[Category: Transcription-transcription inhibitor complex]]

Revision as of 16:29, 21 December 2014

Crystal Structure of the first bromodomain of human BRD4 in complex with a quinazolinone ligand (RVX-208)

4mr4, resolution 1.66Å

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