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Crystal Structure of Protein Lysine Methyltransferase SMYD2 in complex with LLY-507, a Cell-Active, Potent and Selective Inhibitor
Structural highlights
FunctionSMYD2_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 PubMedSMYD2 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. See AlsoReferences
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