7l72: Difference between revisions
No edit summary |
No edit summary |
||
| (One intermediate revision by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal structure of the second bromodomain (BD2) of human BRD3 bound to Ro3280== | ==Crystal structure of the second bromodomain (BD2) of human BRD3 bound to Ro3280== | ||
<StructureSection load='7l72' size='340' side='right'caption='[[7l72]]' scene=''> | <StructureSection load='7l72' size='340' side='right'caption='[[7l72]], [[Resolution|resolution]] 1.50Å' 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=7L72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L72 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7l72]] is a 1 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=7L72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L72 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=7l72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l72 OCA], [https://pdbe.org/7l72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l72 RCSB], [https://www.ebi.ac.uk/pdbsum/7l72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l72 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=79C:4-[(9-CYCLOPENTYL-7,7-DIFLUORO-5-METHYL-6-OXO-6,7,8,9-TETRAHYDRO-5H-PYRIMIDO[4,5-B][1,4]DIAZEPIN-2-YL)AMINO]-3-METHOXY-N-(1-METHYLPIPERIDIN-4-YL)BENZAMIDE'>79C</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=7l72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l72 OCA], [https://pdbe.org/7l72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l72 RCSB], [https://www.ebi.ac.uk/pdbsum/7l72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l72 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/BRD3_HUMAN BRD3_HUMAN] Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BRD3_HUMAN BRD3_HUMAN] Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene.<ref>PMID:18406326</ref> | |||
<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 7l72" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bikowitz M]] | [[Category: Bikowitz M]] | ||
[[Category: Karim MR]] | [[Category: Karim MR]] | ||
[[Category: Schonbrunn E]] | [[Category: Schonbrunn E]] | ||
Latest revision as of 18:39, 18 October 2023
Crystal structure of the second bromodomain (BD2) of human BRD3 bound to Ro3280Crystal structure of the second bromodomain (BD2) of human BRD3 bound to Ro3280
Structural highlights
DiseaseBRD3_HUMAN Note=A chromosomal aberration involving BRD3 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;9)(q14;q34) with NUT which produces a BRD3-NUT fusion protein. FunctionBRD3_HUMAN Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling and interaction with transcription factors. Regulates transcription by promoting the binding of the transcription factor GATA1 to its targets (By similarity). Regulates transcription of the CCND1 gene.[1] 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||