4ynd

From Proteopedia

(Difference between revisions)

Revision as of 08:21, 3 May 2023

The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Structural highlights

4ynd is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. Repression of p53 activity by Smyd2-mediated methylation. Nature. 2006 Nov 30;444(7119):629-32. Epub 2006 Nov 15. PMID:17108971 doi:10.1038/nature05287
↑ Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL. p53 is regulated by the lysine demethylase LSD1. Nature. 2007 Sep 6;449(7158):105-8. PMID:17805299 doi:nature06092
↑ Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics. 2008 Mar;7(3):560-72. Epub 2007 Dec 7. PMID:18065756 doi:10.1074/mcp.M700271-MCP200
↑ Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem. 2010 Nov 26;285(48):37733-40. doi: 10.1074/jbc.M110.137612. Epub, 2010 Sep 24. PMID:20870719 doi:10.1074/jbc.M110.137612
↑ 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. Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. ACS Med Chem Lett. 2015 Apr 29;6(6):695-700. doi: 10.1021/acsmedchemlett.5b00124., eCollection 2015 Jun 11. PMID:26101576 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00124

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ynd"

@@ Line 3: / Line 3: @@
 <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 [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YND FirstGlance]. <br>
+<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>
+</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMYD2, KMT3C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
-<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=4ynd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ynd OCA], [http://pdbe.org/4ynd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ynd RCSB], [http://www.ebi.ac.uk/pdbsum/4ynd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ynd ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 20: @@
 ==See Also==
-*[[Histone methyltransferase|Histone methyltransferase]]
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Algire, M]]
+[[Category: Algire M]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Brown, P J]]
+[[Category: Brown PJ]]
-[[Category: Chiang, G C]]
+[[Category: Chiang GC]]
-[[Category: Guo, J]]
+[[Category: Guo J]]
-[[Category: Jakob, C G]]
+[[Category: Jakob CG]]
-[[Category: Kennedy, S]]
+[[Category: Kennedy S]]
-[[Category: Li, F]]
+[[Category: Li F]]
-[[Category: Pappano, W N]]
+[[Category: Pappano WN]]
-[[Category: Soni, N B]]
+[[Category: Soni NB]]
-[[Category: Sweis, R F]]
+[[Category: Sweis RF]]
-[[Category: Vedadi, M]]
+[[Category: Vedadi M]]
-[[Category: Wang, Z]]
+[[Category: Wang Z]]
-[[Category: Epigenetic]]
-[[Category: H3k36]]
-[[Category: Lysine]]
-[[Category: Methyltransferase]]
-[[Category: P53]]
-[[Category: Smyd2]]
-[[Category: Tranferase-transferase inhibitor complex]]

4ynd

From Proteopedia

Revision as of 08:21, 3 May 2023

The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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