4nue: Difference between revisions
New page: '''Unreleased structure''' The entry 4nue is ON HOLD Authors: Plotnikov, A.N., Joshua, J., Zhou, M.-M. Description: Crystal structure of the first bromodomain of human BRD4 in complex ... |
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==Crystal structure of the first bromodomain of human BRD4 in complex with MS267 inhibitor== | |||
<StructureSection load='4nue' size='340' side='right'caption='[[4nue]], [[Resolution|resolution]] 1.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4nue]] 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=4NUE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NUE 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]] 1.3Å</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=NUE:4-[(E)-(2-AMINO-4-HYDROXY-3,5-DIMETHYLPHENYL)DIAZENYL]-N-(PYRIDIN-2-YL)BENZENESULFONAMIDE'>NUE</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=4nue FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nue OCA], [https://pdbe.org/4nue PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nue RCSB], [https://www.ebi.ac.uk/pdbsum/4nue PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nue 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 == | |||
BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-kappaB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression. | |||
Structure-guided design of potent diazobenzene inhibitors for the BET bromodomains.,Zhang G, Plotnikov AN, Rusinova E, Shen T, Morohashi K, Joshua J, Zeng L, Mujtaba S, Ohlmeyer M, Zhou MM J Med Chem. 2013 Nov 27;56(22):9251-64. doi: 10.1021/jm401334s. Epub 2013 Nov 11. PMID:24144283<ref>PMID:24144283</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4nue" 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: Joshua J]] | |||
[[Category: Plotnikov AN]] | |||
[[Category: Zhou M-M]] | |||