5ttf: Difference between revisions

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-'''Unreleased structure'''
-The entry 5ttf is ON HOLD
+==Crystal structure of catalytic domain of G9a with MS012==
+<StructureSection load='5ttf' size='340' side='right'caption='[[5ttf]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5ttf]] 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=5TTF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TTF 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]] 1.72&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7KZ:N4-(1-METHYLPIPERIDIN-4-YL)-N2-HEXYL-6,7-DIMETHOXYQUINAZOLINE-2,4-DIAMINE'>7KZ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=5ttf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ttf OCA], [https://pdbe.org/5ttf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ttf RCSB], [https://www.ebi.ac.uk/pdbsum/5ttf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ttf ProSAT]</span></td></tr>
+</table>
+== Function ==
+[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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are &gt;30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.
-Authors: DONG, A., ZENG, H., LIU, J., XIONG, Y., BABAULT, N., JIN, J., TEMPEL, W., Bountra, C., Arrowsmith, C.H., Edwards, A.M., WU, H., BROWN, P.J., Structural Genomics Consortium (SGC)
+Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.,Xiong Y, Li F, Babault N, Dong A, Zeng H, Wu H, Chen X, Arrowsmith CH, Brown PJ, Liu J, Vedadi M, Jin J J Med Chem. 2017 Feb 14. doi: 10.1021/acs.jmedchem.6b01645. PMID:28135087<ref>PMID:28135087</ref>
-Description: Crystal structure of catalytic domain of G9a with MS012
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Dong, A]]
+<div class="pdbe-citations 5ttf" style="background-color:#fffaf0;"></div>
-[[Category: Zeng, H]]
-[[Category: Babault, N]]
+==See Also==
-[[Category: Liu, J]]
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
-[[Category: Wu, H]]
+== References ==
-[[Category: Jin, J]]
+<references/>
-[[Category: Bountra, C]]
+__TOC__
-[[Category: Tempel, W]]
+</StructureSection>
-[[Category: Arrowsmith, C.H]]
+[[Category: Homo sapiens]]
-[[Category: Brown, P.J]]
+[[Category: Large Structures]]
-[[Category: Xiong, Y]]
+[[Category: Arrowsmith CH]]
-[[Category: Edwards, A.M]]
+[[Category: BABAULT N]]
-[[Category: Structural Genomics Consortium (Sgc)]]
+[[Category: BROWN PJ]]
+[[Category: Bountra C]]
+[[Category: DONG A]]
+[[Category: Edwards AM]]
+[[Category: JIN J]]
+[[Category: LIU J]]
+[[Category: TEMPEL W]]
+[[Category: WU H]]
+[[Category: XIONG Y]]
+[[Category: ZENG H]]