7t7l: Difference between revisions
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==Structure of human G9a SET-domain (EHMT2) in complex with covalent inhibitor (Compound 1)== | |||
<StructureSection load='7t7l' size='340' side='right'caption='[[7t7l]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7t7l]] is a 4 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=7T7L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T7L 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=G4R:N-(6-methoxy-4-{[1-(propan-2-yl)piperidin-4-yl]amino}-7-[3-(pyrrolidin-1-yl)propoxy]quinazolin-2-yl)prop-2-enamide'>G4R</scene>, <scene name='pdbligand=G5U:~{N}-[6-methoxy-4-[(1-propan-2-ylpiperidin-4-yl)amino]-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-2-yl]propanamide'>G5U</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7t7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t7l OCA], [https://pdbe.org/7t7l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t7l RCSB], [https://www.ebi.ac.uk/pdbsum/7t7l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t7l ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases. | |||
Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.,Park KS, Xiong Y, Yim H, Velez J, Babault N, Kumar P, Liu J, Jin J J Med Chem. 2022 Aug 11;65(15):10506-10522. doi: 10.1021/acs.jmedchem.2c00652. , Epub 2022 Jun 28. PMID:35763668<ref>PMID:35763668</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 7t7l" style="background-color:#fffaf0;"></div> | ||
[[Category: Kumar | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kumar P]] | |||
[[Category: Park K-S]] | |||
Latest revision as of 09:12, 17 October 2024
Structure of human G9a SET-domain (EHMT2) in complex with covalent inhibitor (Compound 1)
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