7l9m
From Proteopedia
(Difference between revisions)
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==Crystal structure of the first bromodomain (BD1) of human BRD4 in complex with bivalent inhibitor GXH-II-083== | ==Crystal structure of the first bromodomain (BD1) of human BRD4 in complex with bivalent inhibitor GXH-II-083== | ||
| - | <StructureSection load='7l9m' size='340' side='right'caption='[[7l9m]]' scene=''> | + | <StructureSection load='7l9m' size='340' side='right'caption='[[7l9m]], [[Resolution|resolution]] 1.45Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L9M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7l9m]] 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=7L9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L9M FirstGlance]. <br> |
| - | </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=7l9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l9m OCA], [https://pdbe.org/7l9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l9m RCSB], [https://www.ebi.ac.uk/pdbsum/7l9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l9m ProSAT]</span></td></tr> | + | </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=XR4:N,N-[(1,19-dioxo-4,7,10,13,16-pentaoxanonadecane-1,19-diyl)di(piperidine-1,4-diyl)]bis(4-{[4-({3-[(tert-butylsulfonyl)amino]-4-chlorophenyl}amino)-5-methylpyrimidin-2-yl]amino}-2-fluorobenzamide)'>XR4</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=7l9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l9m OCA], [https://pdbe.org/7l9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l9m RCSB], [https://www.ebi.ac.uk/pdbsum/7l9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l9m ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization. | ||
| + | |||
| + | Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.,Guan X, Cheryala N, Karim RM, Chan A, Berndt N, Qi J, Georg GI, Schonbrunn E J Med Chem. 2022 Jul 22. doi: 10.1021/acs.jmedchem.2c00453. PMID:35867655<ref>PMID:35867655</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7l9m" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Karim MR]] | [[Category: Karim MR]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn E]] | ||
Revision as of 03:47, 8 September 2022
Crystal structure of the first bromodomain (BD1) of human BRD4 in complex with bivalent inhibitor GXH-II-083
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