View source for 8fvk


==First bromodomain of BRD4 liganded with CCS-1477==
<StructureSection load='8fvk' size='340' side='right'caption='[[8fvk]], [[Resolution|resolution]] 1.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8fvk]] 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=8FVK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FVK 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]] 1.53&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=JHL:(6S)-1-[3,4-bis(fluoranyl)phenyl]-6-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]piperidin-2-one'>JHL</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=8fvk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fvk OCA], [https://pdbe.org/8fvk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fvk RCSB], [https://www.ebi.ac.uk/pdbsum/8fvk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fvk 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 ==
Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.,Shendy NAM, Bikowitz M, Sigua LH, Zhang Y, Mercier A, Khashana Y, Nance S, Liu Q, Delahunty IM, Robinson S, Goel V, Rees MG, Ronan MA, Wang T, Kocak M, Roth JA, Wang Y, Freeman BB, Orr BA, Abraham BJ, Roussel MF, Schonbrunn E, Qi J, Durbin AD Nat Commun. 2024 Apr 25;15(1):3483. doi: 10.1038/s41467-024-47102-0. PMID:38664416<ref>PMID:38664416</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8fvk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bikowitz M]]
[[Category: Schonbrunn E]]