6q3y
From Proteopedia
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(New page: '''Unreleased structure''' The entry 6q3y is ON HOLD Authors: Description: Category: Unreleased Structures) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i== | |
| + | <StructureSection load='6q3y' size='340' side='right'caption='[[6q3y]], [[Resolution|resolution]] 1.20Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6q3y]] 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=6Q3Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q3Y 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]] 1.2Å</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=HG5:(7~{R})-2-[[2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl]amino]-7-ethyl-5-methyl-8-(phenylmethyl)-7~{H}-pteridin-6-one'>HG5</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=6q3y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3y OCA], [https://pdbe.org/6q3y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q3y RCSB], [https://www.ebi.ac.uk/pdbsum/6q3y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3y 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 == | ||
| + | Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-me thylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity. | ||
| - | + | Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.,Watts E, Heidenreich D, Tucker E, Raab M, Strebhardt K, Chesler L, Knapp S, Bellenie B, Hoelder S J Med Chem. 2019 Feb 21. doi: 10.1021/acs.jmedchem.8b01947. PMID:30789735<ref>PMID:30789735</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6q3y" 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: Heidenreich D]] | ||
| + | [[Category: Hoelder S]] | ||
| + | [[Category: Knapp S]] | ||
| + | [[Category: Watts E]] | ||
Current revision
Crystal structure of the first bromodomain of human BRD4 in complex with the inhibitor 16i
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