8zmq: Difference between revisions
m Protected "8zmq" [edit=sysop:move=sysop] |
No edit summary |
||
| (One intermediate revision by the same user not shown) | |||
| Line 1: | Line 1: | ||
==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]] 2.20Å' 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]] 2.2Å</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) > 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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8zmq" style="background-color:#fffaf0;"></div> | ||
[[Category: Hu | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: Xu | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hu Q]] | ||
[[Category: | [[Category: Li J]] | ||
[[Category: Wu X]] | |||
[[Category: Xu H]] | |||
[[Category: Xu Y]] | |||
[[Category: Zhang C]] | |||
[[Category: Zhang Y]] | |||
[[Category: Zhao X]] | |||
[[Category: Zhu R]] | |||
Latest revision as of 23:04, 11 December 2024
Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the inhibitor Y13190Crystal Structure of the second bromodomain of human BRD4 BD2 in complex with the inhibitor Y13190
Structural highlights
DiseaseBRD4_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.[1] [2] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedPan-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) > 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. 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||