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Crystal structure of SMYD3 with diperodon R enantiomer bound to allosteric site
Structural highlights
FunctionSMYD3_HUMAN Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.[1] [2] Publication Abstract from PubMedSMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase 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 using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 muM). 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 HSP90-SMYD3 binding was confirmed ( K D = 13 muM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action. Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase.,Talibov VO, Fabini E, FitzGerald E, Tedesco D, Eriksson D, Talu MJ, Rachman MM, Mihalic F, Manoni E, Naldi M, Sanese P, Forte G, Signorile ML, Barril X, Simone C, Bartolini M, Dobritzsch D, Del Rio A, Danielson UH Chembiochem. 2021 Jan 5. doi: 10.1002/cbic.202000736. PMID:33400854[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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