Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase
Copyright policy )Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase
AbstractSMYD3 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 (KD=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 (KD=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.
570, Biophysics, Drug Evaluation, Preclinical, 610, Molecular Dynamics Simulation, Ligands, Piperidines, Surface plasmon resonance, Cell Line, Tumor, Humans, HSP90 Heat-Shock Proteins, diperodon, biophysical methods, SMYD3, Binding Sites, Lysine methyl transferase, screening, epigenetic enzymes, Stereoisomerism, Histone-Lysine N-Methyltransferase, Full Papers, Biofysik, SMYD3 biology, Kinetics, ligand discovery, SMYD3 biology; biophysical methods; epigenetic enzymes; ligand discovery, Allosteric Site, Protein Binding
570, Biophysics, Drug Evaluation, Preclinical, 610, Molecular Dynamics Simulation, Ligands, Piperidines, Surface plasmon resonance, Cell Line, Tumor, Humans, HSP90 Heat-Shock Proteins, diperodon, biophysical methods, SMYD3, Binding Sites, Lysine methyl transferase, screening, epigenetic enzymes, Stereoisomerism, Histone-Lysine N-Methyltransferase, Full Papers, Biofysik, SMYD3 biology, Kinetics, ligand discovery, SMYD3 biology; biophysical methods; epigenetic enzymes; ligand discovery, Allosteric Site, Protein Binding
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).11 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!