3k5k

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{{STRUCTURE_3k5k| PDB=3k5k | SCENE= }}
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==Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent Inhibitor of Histone Lysine Methyltransferase, G9a==
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===Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent Inhibitor of Histone Lysine Methyltransferase, G9a===
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<StructureSection load='3k5k' size='340' side='right' caption='[[3k5k]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
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{{ABSTRACT_PUBMED_19891491}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3k5k]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K5K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3K5K FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DXQ:7-[3-(DIMETHYLAMINO)PROPOXY]-6-METHOXY-2-(4-METHYL-1,4-DIAZEPAN-1-YL)-N-(1-METHYLPIPERIDIN-4-YL)QUINAZOLIN-4-AMINE'>DXQ</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EHMT2, BAT8, C6orf30, G9A, KMT1C, NG36 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3k5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3k5k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3k5k RCSB], [http://www.ebi.ac.uk/pdbsum/3k5k PDBsum]</span></td></tr>
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</table>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k5/3k5k_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as a potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling.
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==Function==
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Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a.,Liu F, Chen X, Allali-Hassani A, Quinn AM, Wasney GA, Dong A, Barsyte D, Kozieradzki I, Senisterra G, Chau I, Siarheyeva A, Kireev DB, Jadhav A, Herold JM, Frye SV, Arrowsmith CH, Brown PJ, Simeonov A, Vedadi M, Jin J J Med Chem. 2009 Dec 24;52(24):7950-3. PMID:19891491<ref>PMID:19891491</ref>
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[[http://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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3k5k]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3K5K OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:019891491</ref><references group="xtra"/><references/>
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*[[Histone methyltransferase|Histone methyltransferase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Histone-lysine N-methyltransferase]]
[[Category: Histone-lysine N-methyltransferase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Allali-Hassani,A.]]
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[[Category: Allali-Hassani,A]]
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[[Category: Arrowsmith,C H.]]
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[[Category: Arrowsmith,C H]]
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[[Category: Bochkarev,A.]]
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[[Category: Bochkarev,A]]
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[[Category: Bountra,C.]]
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[[Category: Bountra,C]]
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[[Category: Brown,P J.]]
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[[Category: Brown,P J]]
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[[Category: Chau,I.]]
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[[Category: Chau,I]]
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[[Category: Chen,X.]]
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[[Category: Chen,X]]
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[[Category: Dong,A.]]
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[[Category: Dong,A]]
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[[Category: Edwards,A M.]]
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[[Category: Edwards,A M]]
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[[Category: Frye,S V.]]
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[[Category: Frye,S V]]
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[[Category: Jin,J.]]
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[[Category: Jin,J]]
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[[Category: Liu,F.]]
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[[Category: Liu,F]]
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[[Category: Senisterra,G.]]
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[[Category: Senisterra,G]]
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[[Category: Vedadi,M.]]
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[[Category: Vedadi,M]]
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[[Category: Wasney,G A.]]
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[[Category: Wasney,G A]]
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[[Category: Weigelt,J.]]
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[[Category: Weigelt,J]]
[[Category: Ank repeat]]
[[Category: Ank repeat]]
[[Category: Chromatin regulator]]
[[Category: Chromatin regulator]]
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[[Category: Sgc]]
[[Category: Sgc]]
[[Category: Structural genomic]]
[[Category: Structural genomic]]
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[[Category: Structural genomics consortium]]
 
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 17:17, 18 December 2014

Discovery of a 2,4-Diamino-7-aminoalkoxy-quinazoline as a Potent Inhibitor of Histone Lysine Methyltransferase, G9a

3k5k, resolution 1.70Å

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