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==Crystal structure of the first bromodomain of human BRD4 in complex with SB-251527== | ==Crystal structure of the first bromodomain of human BRD4 in complex with SB-251527== | ||
<StructureSection load='4o7f' size='340' side='right' caption='[[4o7f]], [[Resolution|resolution]] 1.80Å' scene=''> | <StructureSection load='4o7f' size='340' side='right'caption='[[4o7f]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4o7f]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4o7f]] 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=4O7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4O7F FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2RQ:4-[4-(4-FLUOROPHENYL)-1-(PIPERIDIN-4-YL)-1H-IMIDAZOL-5-YL]-2-(2-METHOXYPHENOXY)PYRIMIDINE'>2RQ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2RQ:4-[4-(4-FLUOROPHENYL)-1-(PIPERIDIN-4-YL)-1H-IMIDAZOL-5-YL]-2-(2-METHOXYPHENOXY)PYRIMIDINE'>2RQ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr> | |||
<tr | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4o7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4o7f OCA], [https://pdbe.org/4o7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4o7f RCSB], [https://www.ebi.ac.uk/pdbsum/4o7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4o7f ProSAT]</span></td></tr> | ||
</table> | |||
<table> | |||
== Disease == | == 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 == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 18: | Line 18: | ||
Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.,Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E ACS Chem Biol. 2014 Mar 13. PMID:24568369<ref>PMID:24568369</ref> | Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.,Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E ACS Chem Biol. 2014 Mar 13. PMID:24568369<ref>PMID:24568369</ref> | ||
From | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4o7f" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Ember | [[Category: Large Structures]] | ||
[[Category: Schonbrunn | [[Category: Ember SW]] | ||
[[Category: Watts | [[Category: Schonbrunn E]] | ||
[[Category: Zhu | [[Category: Watts C]] | ||
[[Category: Zhu J-Y]] | |||
Latest revision as of 20:08, 20 September 2023
Crystal structure of the first bromodomain of human BRD4 in complex with SB-251527Crystal structure of the first bromodomain of human BRD4 in complex with SB-251527
Structural highlights
DiseaseBRD4_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] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedMembers of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation, and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 (BRD4-1) against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK1 inhibitor BI2536 and the JAK2 inhibitor TG101209 displayed strongest inhibitory potential against BRD4 (IC50 = 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site, suggesting that BET proteins are potential off-targets of diverse kinase inhibitors. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual-activity BET-kinase inhibitors. Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors.,Ember SW, Zhu JY, Olesen SH, Martin MP, Becker A, Berndt N, Georg GI, Schonbrunn E ACS Chem Biol. 2014 Mar 13. PMID:24568369[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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