6uwu
From Proteopedia
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- | '''Unreleased structure''' | ||
- | + | ==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516== | |
+ | <StructureSection load='6uwu' size='340' side='right'caption='[[6uwu]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
+ | == Structural highlights == | ||
+ | <table><tr><td colspan='2'>[[6uwu]] 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=6UWU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UWU FirstGlance]. <br> | ||
+ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</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=QKP:2-{4-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy]-3,5-dimethylphenyl}-5,7-dimethoxy-4H-1-benzopyran-4-one'>QKP</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=6uwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwu OCA], [https://pdbe.org/6uwu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uwu RCSB], [https://www.ebi.ac.uk/pdbsum/6uwu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwu ProSAT]</span></td></tr> | ||
+ | </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-containing protein 4 (BRD4) represents a promising drug target for anti-inflammatory therapeutics. Herein, we report the design, synthesis, and pharmacological evaluation of novel chromone derivatives via scaffold hopping to discover a new class of orally bioavailable BRD4 selective inhibitors. Two potent BRD4 bromodomain 1 (BD1) selective inhibitors 44 (ZL0513) and 45 (ZL0516) have been discovered with high binding affinity (IC50 values of 67~84 nM) and good selectivity over other BRD family proteins and distant BD-containing proteins. Both compounds significantly inhibited the expression of Toll-like receptor (TLR3)-induced inflammatory genes in vitro and airway inflammation in murine models. The cocrystal structure of 45 in complex with human BRD4 BD1 at a high resolution of 2.0 A has been solved, offering a solid structural basis for its binding validation and further structure-based optimization. These BRD4 BD1 inhibitors demonstrated impressive in vivo efficacy and overall promising pharmacokinetic properties, indicating their therapeutic potential for the treatment of inflammatory diseases. | ||
- | + | Discovery of Orally Bioavailable Chromone Derivatives as Potent and Selective BRD4 Inhibitors: Scaffolding Hopping, Optimization and Pharmacological Evaluation.,Liu Z, Chen H, Wang P, Li Y, Wold EA, Leonard PG, Joseph S, Brasier AR, Tian B, Zhou J J Med Chem. 2020 Apr 7. doi: 10.1021/acs.jmedchem.0c00035. PMID:32255647<ref>PMID:32255647</ref> | |
- | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
- | [[Category: | + | </div> |
+ | <div class="pdbe-citations 6uwu" style="background-color:#fffaf0;"></div> | ||
+ | |||
+ | ==See Also== | ||
+ | *[[Bromodomain-containing protein 3D structures|Bromodomain-containing protein 3D structures]] | ||
+ | == References == | ||
+ | <references/> | ||
+ | __TOC__ | ||
+ | </StructureSection> | ||
+ | [[Category: Homo sapiens]] | ||
+ | [[Category: Large Structures]] | ||
+ | [[Category: Joseph S]] | ||
+ | [[Category: Leonard PG]] |
Current revision
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516
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