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==Crystal structure of the first bromodomain (BD1) of human BRD2 bound to BI2536== | ==Crystal structure of the first bromodomain (BD1) of human BRD2 bound to BI2536== | ||
<StructureSection load='7lai' size='340' side='right'caption='[[7lai]]' scene=''> | <StructureSection load='7lai' size='340' side='right'caption='[[7lai]], [[Resolution|resolution]] 1.85Å' 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=7LAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LAI FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lai]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LAI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LAI 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=7lai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lai OCA], [https://pdbe.org/7lai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lai RCSB], [https://www.ebi.ac.uk/pdbsum/7lai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lai 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=R78:4-{[(7R)-8-CYCLOPENTYL-7-ETHYL-5-METHYL-6-OXO-5,6,7,8-TETRAHYDROPTERIDIN-2-YL]AMINO}-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>R78</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7lai FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lai OCA], [https://pdbe.org/7lai PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lai RCSB], [https://www.ebi.ac.uk/pdbsum/7lai PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lai ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
BRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially. | |||
Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.,Karim RM, Bikowitz MJ, Chan A, Zhu JY, Grassie D, Becker A, Berndt N, Gunawan S, Lawrence NJ, Schonbrunn E J Med Chem. 2021 Nov 11;64(21):15772-15786. doi: 10.1021/acs.jmedchem.1c01096., Epub 2021 Oct 28. PMID:34710325<ref>PMID:34710325</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lai" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bikowitz M]] | [[Category: Bikowitz, M]] | ||
[[Category: Karim | [[Category: Karim, M R]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn, E]] | ||
[[Category: Bet]] | |||
[[Category: Dual brd-kinase inhibitor]] | |||
[[Category: Erk5]] | |||
[[Category: Gene regulation]] | |||
Revision as of 17:13, 17 November 2021
Crystal structure of the first bromodomain (BD1) of human BRD2 bound to BI2536Crystal structure of the first bromodomain (BD1) of human BRD2 bound to BI2536
Structural highlights
Publication Abstract from PubMedBRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially. Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors.,Karim RM, Bikowitz MJ, Chan A, Zhu JY, Grassie D, Becker A, Berndt N, Gunawan S, Lawrence NJ, Schonbrunn E J Med Chem. 2021 Nov 11;64(21):15772-15786. doi: 10.1021/acs.jmedchem.1c01096., Epub 2021 Oct 28. PMID:34710325[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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