View source for 4ynd


==The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2==
<StructureSection load='4ynd' size='340' side='right'caption='[[4ynd]], [[Resolution|resolution]] 2.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ynd]] is a 1 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=4YND OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YND 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]] 2.79&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4GQ:N-CYCLOHEXYL-N~3~-[2-(3,4-DICHLOROPHENYL)ETHYL]-N-(2-{[(2R)-2-HYDROXY-2-(3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-8-YL)ETHYL]AMINO}ETHYL)-BETA-ALANINAMIDE'>4GQ</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=4ynd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynd OCA], [https://pdbe.org/4ynd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ynd RCSB], [https://www.ebi.ac.uk/pdbsum/4ynd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynd ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SMYD2_HUMAN SMYD2_HUMAN] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.<ref>PMID:17108971</ref> <ref>PMID:17805299</ref> <ref>PMID:18065756</ref> <ref>PMID:20870719</ref> 
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== Publication Abstract from PubMed ==
A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.,Sweis RF, Wang Z, Algire M, Arrowsmith CH, Brown PJ, Chiang GG, Guo J, Jakob CG, Kennedy S, Li F, Maag D, Shaw B, Soni NB, Vedadi M, Pappano WN ACS Med Chem Lett. 2015 Apr 29;6(6):695-700. doi: 10.1021/acsmedchemlett.5b00124., eCollection 2015 Jun 11. PMID:26101576<ref>PMID:26101576</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4ynd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Algire M]]
[[Category: Arrowsmith CH]]
[[Category: Brown PJ]]
[[Category: Chiang GC]]
[[Category: Guo J]]
[[Category: Jakob CG]]
[[Category: Kennedy S]]
[[Category: Li F]]
[[Category: Pappano WN]]
[[Category: Soni NB]]
[[Category: Sweis RF]]
[[Category: Vedadi M]]
[[Category: Wang Z]]