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Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase
Author(s) -
Talibov Vladimir O.,
Fabini Edoardo,
FitzGerald Edward A.,
Tedesco Daniele,
Cederfelt Daniela,
Talu Martin J.,
Rachman Moira M.,
Mihalic Filip,
Mai Elisabetta,
Naldi Marina,
Sanese Paola,
Forte Giovanna,
Lepore Signorile Martina,
Barril Xavier,
Simone Cristiano,
Bartolini Manuela,
Dobritzsch Doreen,
Del Rio Alberto,
Danielson U. Helena
Publication year - 2021
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.202000736
Subject(s) - allosteric regulation , druggability , methyltransferase , binding site , drug discovery , ligand (biochemistry) , chemistry , biology , computational biology , epigenetics , allosteric enzyme , biochemistry , enzyme , methylation , receptor , gene
SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug‐like compounds was screened in a biosensor‐based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined ( K D =42 and 84 μM, respectively). Co‐crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C‐terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3–HSP90 binding was confirmed ( K D =13 μM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.