7la9: Difference between revisions
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==Crystal structure of the first bromodomain (BD1) of human BRD4 (BRD4-1) in complex with bivalent inhibitor NC-III-49-1== | ==Crystal structure of the first bromodomain (BD1) of human BRD4 (BRD4-1) in complex with bivalent inhibitor NC-III-49-1== | ||
<StructureSection load='7la9' size='340' side='right'caption='[[7la9]]' scene=''> | <StructureSection load='7la9' size='340' side='right'caption='[[7la9]], [[Resolution|resolution]] 2.20Å' 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=7LA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LA9 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7la9]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LA9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LA9 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=7la9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7la9 OCA], [https://pdbe.org/7la9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7la9 RCSB], [https://www.ebi.ac.uk/pdbsum/7la9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7la9 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=XR7:N,N-(oxybis{(ethane-2,1-diyl)oxyethane-2,1-diyloxy[3-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-4,1-phenylene]})di(ethane-1-sulfonamide)'>XR7</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=7la9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7la9 OCA], [https://pdbe.org/7la9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7la9 RCSB], [https://www.ebi.ac.uk/pdbsum/7la9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7la9 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 7la9" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Karim | [[Category: Karim, M R]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn, E]] | ||
[[Category: Bet]] | |||
[[Category: Dual brd-kinase inhibitor]] | |||
[[Category: Erk5]] | |||
[[Category: Transcription-transcription inhibitor complex]] | |||
Revision as of 07:59, 3 August 2022
Crystal structure of the first bromodomain (BD1) of human BRD4 (BRD4-1) in complex with bivalent inhibitor NC-III-49-1Crystal structure of the first bromodomain (BD1) of human BRD4 (BRD4-1) in complex with bivalent inhibitor NC-III-49-1
Structural highlights
Disease[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.[1] [2] Function[BRD4_HUMAN] Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedBromodomain 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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