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4wuy

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Revision as of 02:01, 11 March 2017

Crystal Structure of Protein Lysine Methyltransferase SMYD2 in complex with LLY-507, a Cell-Active, Potent and Selective Inhibitor

Structural highlights

4wuy is a 1 chain structure. 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

SMYD2 is a lysine methyltransferase that catalyzes the mono-methylation of several protein substrates including p53. SMYD2 is over-expressed in a significant percentage of esophageal squamous primary carcinomas and that over-expression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell active, potent small molecule inhibitor of SMYD2. LLY-507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63A resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells, as measured by reduction of SMYD2-induced mono-methylation of p53 K370 at sub-micromolar doses. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics shows that cellular global histone methylation levels are not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci, and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types which display amplification and/or over-expression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes.

LLY-507, a Cell-Active, Potent and Selective Inhibitor of Protein Lysine Methyltransferase SMYD2.,Nguyen H, Allali-Hassani A, Antonysamy S, Chang S, Chen LH, Curtis C, Emtage S, Fan L, Gheyi T, Li F, Liu S, Martin JR, Mendel D, Olsen JB, Pelletier L, Shatseva T, Wu S, Zhang FF, Arrowsmith CH, Brown PJ, Campbell RM, Garcia BA, Barsyte-Lovejoy D, Mader M, Vedadi M J Biol Chem. 2015 Mar 30. pii: jbc.M114.626861. PMID:25825497^[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
↑ Nguyen H, Allali-Hassani A, Antonysamy S, Chang S, Chen LH, Curtis C, Emtage S, Fan L, Gheyi T, Li F, Liu S, Martin JR, Mendel D, Olsen JB, Pelletier L, Shatseva T, Wu S, Zhang FF, Arrowsmith CH, Brown PJ, Campbell RM, Garcia BA, Barsyte-Lovejoy D, Mader M, Vedadi M. LLY-507, a Cell-Active, Potent and Selective Inhibitor of Protein Lysine Methyltransferase SMYD2. J Biol Chem. 2015 Mar 30. pii: jbc.M114.626861. PMID:25825497 doi:http://dx.doi.org/10.1074/jbc.M114.626861

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/4wuy"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of Protein Lysine Methyltransferase SMYD2 in complex with LLY-507, a Cell-Active, Potent and Selective Inhibitor==
 <StructureSection load='4wuy' size='340' side='right' caption='[[4wuy]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[4wuy]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WUY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WUY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3UJ:5-CYANO-2-{4-[2-(3-METHYL-1H-INDOL-1-YL)ETHYL]PIPERAZIN-1-YL}-N-[3-(PYRROLIDIN-1-YL)PROPYL]BIPHENYL-3-CARBOXAMIDE'>3UJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wuy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wuy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wuy RCSB], [http://www.ebi.ac.uk/pdbsum/4wuy PDBsum]</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=4wuy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wuy OCA], [http://pdbe.org/4wuy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wuy RCSB], [http://www.ebi.ac.uk/pdbsum/4wuy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wuy ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4wuy" style="background-color:#fffaf0;"></div>
 ==See Also==

4wuy

From Proteopedia

Revision as of 02:01, 11 March 2017

Crystal Structure of Protein Lysine Methyltransferase SMYD2 in complex with LLY-507, a Cell-Active, Potent and Selective Inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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