The lysine methyltransferase SMYD2 is a maturing target in the area of epigenetics. Known substrates for SMYD2 include histone H3 and the tumor suppressor proteins p53 and Rb. Furthermore, SMYD2 overexpression associates with poor survival in esophageal and other cancers and so represents a potential target for anticancer drug development. We found that several �bisubstrate� class inhibitors originally targeted against arginine methyltransferases inhibit SMYD2 in the 200 nanoM to low microM IC50 range and then devised a method to obtain high resolution (<2�) co-complex structures of these compounds with SMYD2.This class of inhibitors was found to occupy both the SAM cofactor binding site and the channel that orients substrate lysine sidechains for methyl group transfer. Here we describe in detail the important interactions between SMYD2 and the bisubstrate type inhibitors and how those structural details may be used to design inhibitors with more drug-like properties.

High resolution structures of SMYD2 in complex with inhibitors that occupy the lysine substrate channel and SAM cofactor domain

246th National Meeting (2013)

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