4WUY

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

Summary for 4WUY

• Entry DOI: 10.2210/pdb4wuy/pdb
• Descriptor: N-lysine methyltransferase SMYD2, 5-cyano-2'-{4-[2-(3-methyl-1H-indol-1-yl)ethyl]piperazin-1-yl}-N-[3-(pyrrolidin-1-yl)propyl]biphenyl-3-carboxamide, S-ADENOSYL-L-HOMOCYSTEINE, ... (6 entities in total)
• Functional Keywords: smyd2 - lly-507, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : Q9NRG4
• Total number of polymer chains: 1
• Total formula weight: 52272.22

Authors

Nguyen, H.,Allali-Hassani, A.,Antonysamy, S.,Chang, S.,Chen, L.H.,Curtis, C.,Emtage, S.,Fan, L.,Gheyi, T.,Li, F.,Liu, S.,Martin, J.R.,Mendel, D.,Olsen, J.B.,Pelletier, L.,Shatseva, T.,Wu, S.,Zhang, F.F.,Arrowsmith, C.H.,Brown, P.J.,Campbell, R.M.,Garcia, B.A.,Barsyte-Lovejoy, D.,Mader, M.,Vedadi, M. (deposition date: 2014-11-04, release date: 2015-04-08, Last modification date: 2023-12-27)

Primary citation

Nguyen, H.,Allali-Hassani, A.,Antonysamy, S.,Chang, S.,Chen, L.H.,Curtis, C.,Emtage, S.,Fan, L.,Gheyi, T.,Li, F.,Liu, S.,Martin, J.R.,Mendel, D.,Olsen, J.B.,Pelletier, L.,Shatseva, T.,Wu, S.,Zhang, F.F.,Arrowsmith, C.H.,Brown, P.J.,Campbell, R.M.,Garcia, B.A.,Barsyte-Lovejoy, D.,Mader, M.,Vedadi, M.
LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2.
J.Biol.Chem., 290:13641-13653, 2015

PubMed Abstract: SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression 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 1.63-Å 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 monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were 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 that display amplification and/or overexpression 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.

PubMed: 25825497
DOI: 10.1074/jbc.M114.626861

Experimental method

X-RAY DIFFRACTION (1.63 Å)