View source for 6viy


==BRD2_Bromodomain2 complex with pyrrolopyridone compound 27==
<StructureSection load='6viy' size='340' side='right'caption='[[6viy]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6viy]] 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=6VIY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VIY 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]] 1.904&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QYY:4-[2-(2,6-dimethylphenoxy)-5-(ethylsulfonyl)phenyl]-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide'>QYY</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=6viy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6viy OCA], [https://pdbe.org/6viy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6viy RCSB], [https://www.ebi.ac.uk/pdbsum/6viy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6viy ProSAT]</span></td></tr>
</table>
== 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;">
== Publication Abstract from PubMed ==
The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (&gt;70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (~40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).

Discovery of N-ethyl-4-[2-(4-fluoro-2,6-dimethyl-phenoxy)-5-(1-hydroxy-1-methyl-ethyl)phenyl]- 6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (ABBV-744), a BET bromodomain inhibitor with selectivity for the second bromodomain.,Sheppard GS, Wang L, Fidanze SD, Hasvold LA, Liu D, Pratt JK, Park CH, Longenecker KL, Qiu W, Torrent M, Kovar P, Bui M, Faivre EJ, Huang X, Lin X, Wilcox D, Zhang L, Shen Y, Albert DH, Magoc TJ, Rajaraman G, Kati WM, McDaniel KF J Med Chem. 2020 Apr 23. doi: 10.1021/acs.jmedchem.0c00628. PMID:32324999<ref>PMID:32324999</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6viy" 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: Longenecker KL]]
[[Category: Park CH]]
[[Category: Qiu W]]