5jwm
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Bivalent BET Bromodomain Inhibition== | |
| + | <StructureSection load='5jwm' size='340' side='right'caption='[[5jwm]], [[Resolution|resolution]] 1.71Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5jwm]] 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=5JWM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JWM 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]] 1.71Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6ON:2-[(9~{S})-7-(4-CHLOROPHENYL)-4,5,13-TRIMETHYL-3-THIA-1,8,11,12-TETRAZATRICYCLO[8.3.0.0^{2,6}]TRIDECA-2(6),4,7,10,12-PENTAEN-9-YL]-~{N}-[2-[2-[2-[2-[2-[2-[2-[2-[2-[(9~{S})-7-(4-CHLOROPHENYL)-4,5,13-TRIMETHYL-3-THIA-1,8,11,12-TETRAZATRICYCLO[8.3.0.0^{2,6}]TRIDECA-2(6),4,7,10,12-PENTAEN-9-YL]ETHANOYLAMINO]ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHOXY]ETHYL]ETHANAMIDE'>6ON</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=5jwm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jwm OCA], [https://pdbe.org/5jwm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jwm RCSB], [https://www.ebi.ac.uk/pdbsum/5jwm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jwm 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 == | ||
| + | Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors. All reported antagonists of the BET protein BRD4 bind in a monovalent fashion. Here we describe, to our knowledge for the first time, a bivalent BET bromodomain inhibitor-MT1-which has unprecedented potency. Biophysical and biochemical studies suggest MT1 is an intramolecular bivalent BRD4 binder that is more than 100-fold more potent, in cellular assays, than the corresponding monovalent antagonist, JQ1. MT1 significantly (P < 0.05) delayed leukemia progression in mice, as compared to JQ1. These data qualify a powerful chemical probe for BET bromodomains and a rationale for further development of multidomain inhibitors of epigenetic reader proteins. | ||
| - | + | Design and characterization of bivalent BET inhibitors.,Tanaka M, Roberts JM, Seo HS, Souza A, Paulk J, Scott TG, DeAngelo SL, Dhe-Paganon S, Bradner JE Nat Chem Biol. 2016 Dec;12(12):1089-1096. doi: 10.1038/nchembio.2209. Epub 2016, Oct 24. PMID:27775715<ref>PMID:27775715</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5jwm" 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: Dhe-Paganon S]] | ||
| + | [[Category: Seo H-S]] | ||
Current revision
Bivalent BET Bromodomain Inhibition
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