View source for 6uvj


==Cocrystal of BRD4(D1) with a methyl carbamate thiazepane inhibitor==
<StructureSection load='6uvj' size='340' side='right'caption='[[6uvj]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6uvj]] 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=6UVJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UVJ 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]] 1.38&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=QJ1:methyl+(7S)-7-(thiophen-2-yl)-1,4-thiazepane-4-carboxylate'>QJ1</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=6uvj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uvj OCA], [https://pdbe.org/6uvj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uvj RCSB], [https://www.ebi.ac.uk/pdbsum/6uvj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uvj 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).
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== Publication Abstract from PubMed ==
Fragment-based ligand discovery has been successful in targeting diverse proteins. Despite drug-like molecules having more 3D character, traditional fragment libraries are largely composed of flat, aromatic fragments. The use of 3D-enriched fragments for enhancing library diversity is underexplored especially against protein-protein interactions. Here, we evaluate using 3D-enriched fragments against bromodomains. Bromodomains are highly ligandable, but selectivity remains challenging, particularly for bromodomain and extraterminal (BET) family bromodomains. We screened a 3D-enriched fragment library against BRD4(D1) via (1)H CPMG NMR with a protein-observed (19)F NMR secondary assay. The screen led to 29% of the hits that are selective over two related bromodomains, BRDT(D1) and BPTF, and the identification of underrepresented chemical bromodomain inhibitor scaffolds. Initial structure-activity relationship studies guided by X-ray crystallography led to a ligand-efficient thiazepane, with good selectivity and affinity for BET bromodomains. These results suggest that the incorporation of 3D-enriched fragments to increase library diversity can benefit bromodomain screening.

Evaluating the Advantages of Using 3D-Enriched Fragments for Targeting BET Bromodomains.,Johnson JA, Nicolaou CA, Kirberger SE, Pandey AK, Hu H, Pomerantz WCK ACS Med Chem Lett. 2019 Nov 22;10(12):1648-1654. doi:, 10.1021/acsmedchemlett.9b00414. eCollection 2019 Dec 12. PMID:31857841<ref>PMID:31857841</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6uvj" 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: Johnson JA]]
[[Category: Pomerantz WCK]]