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| ==Structure of human G9a SET-domain (EHMT2) in complex with covalent inhibitor (Compound 1)== | | ==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=''> | | <StructureSection load='7t7l' size='340' side='right'caption='[[7t7l]]' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7t7l]] is a 4 chain structure. 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> | | <table><tr><td colspan='2'>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='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-yl)piperidin-4-yl]amino}-7-[3-(pyrrolidin-1-yl)propoxy]quinazolin-2-yl)propanamide'>G5U</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | | </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> |
| <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> | | </table> |
| == Function ==
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| [[https://www.uniprot.org/uniprot/EHMT2_HUMAN EHMT2_HUMAN]] Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.<ref>PMID:8457211</ref> <ref>PMID:11316813</ref> <ref>PMID:18438403</ref> <ref>PMID:20118233</ref> <ref>PMID:22387026</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| 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.
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| 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 Jun 28. doi: 10.1021/acs.jmedchem.2c00652. PMID:35763668<ref>PMID:35763668</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7t7l" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Kumar, P]] | | [[Category: Kumar P]] |
| [[Category: Park, K S]] | | [[Category: Park K-S]] |
| [[Category: Covalent inhibitor]]
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| [[Category: G9a]]
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| [[Category: Gene regulation]]
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