6uwu
From Proteopedia
(Difference between revisions)
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==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516== | ==Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516== | ||
| - | <StructureSection load='6uwu' size='340' side='right'caption='[[6uwu]]' scene=''> | + | <StructureSection load='6uwu' size='340' side='right'caption='[[6uwu]], [[Resolution|resolution]] 2.00Å' 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=6UWU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6UWU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uwu]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://proteopedia.org/fgij/fg.htm?mol=6UWU FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6uwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwu OCA], [http://pdbe.org/6uwu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwu RCSB], [http://www.ebi.ac.uk/pdbsum/6uwu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwu 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=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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRD4, HUNK1 ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6uwu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uwu OCA], [http://pdbe.org/6uwu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6uwu RCSB], [http://www.ebi.ac.uk/pdbsum/6uwu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6uwu ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[http://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 == | ||
| + | [[http://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> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6uwu" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Joseph S]] | + | [[Category: Joseph, S]] |
| - | [[Category: Leonard | + | [[Category: Leonard, P G]] |
| + | [[Category: Bromodomain]] | ||
| + | [[Category: Complex]] | ||
| + | [[Category: Gene regulation]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 06:38, 6 May 2020
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor ZL0516
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