8zmq: Difference between revisions

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

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-'''Unreleased structure'''
-The entry 8zmq is ON HOLD
+==Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the inhibitor Y13190==
+<StructureSection load='8zmq' size='340' side='right'caption='[[8zmq]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8zmq]] is a 20 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=8ZMQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ZMQ 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]] 2.2&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1L12:2-[2-(1-adamantyl)-4-ethyl-1~{H}-imidazol-5-yl]-7-[2-(4-fluoranyl-2,6-dimethyl-phenoxy)-5-(2-oxidanylpropan-2-yl)phenyl]-5-methyl-furo[3,2-c]pyridin-4-one'>A1L12</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=8zmq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zmq OCA], [https://pdbe.org/8zmq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zmq RCSB], [https://www.ebi.ac.uk/pdbsum/8zmq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zmq 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 ==
+Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor 12 (XY153), we successfully identified 16o (XY221) as the first BRD4 BD2-selective inhibitor. 16o demonstrated potent binding affinity for BRD4 BD2 (IC(50) = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of 16o was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. 16o exhibited good liver microsomal stability (T(1/2) &gt; 120 min) and pharmacokinetic properties (F = 13.1%). These data indicate that 16o may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research.
-Authors: Li, J., Hu, Q., Xu, H., Zhao, X., Zhang, C., Zhu, R., Wu, X., Zhang, Y., Xu, Y.
+Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.,Li J, Hu Q, Zhu R, Dong R, Shen H, Hu J, Zhang C, Zhang X, Xu T, Xiang Q, Zhang Y, Lin B, Zhao L, Wu X, Xu Y J Med Chem. 2024 Nov 27. doi: 10.1021/acs.jmedchem.4c02516. PMID:39602227<ref>PMID:39602227</ref>
-Description: Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the inhibitor Y13190
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhang, C]]
+<div class="pdbe-citations 8zmq" style="background-color:#fffaf0;"></div>
-[[Category: Hu, Q]]
+== References ==
-[[Category: Zhu, R]]
+<references/>
-[[Category: Zhang, Y]]
+__TOC__
-[[Category: Xu, Y]]
+</StructureSection>
-[[Category: Wu, X]]
+[[Category: Homo sapiens]]
-[[Category: Zhao, X]]
+[[Category: Large Structures]]
-[[Category: Xu, H]]
+[[Category: Hu Q]]
-[[Category: Li, J]]
+[[Category: Li J]]
+[[Category: Wu X]]
+[[Category: Xu H]]
+[[Category: Xu Y]]
+[[Category: Zhang C]]
+[[Category: Zhang Y]]
+[[Category: Zhao X]]
+[[Category: Zhu R]]