Login / Signup

Venglustat Inhibits Protein N-Terminal Methyltransferase 1 in a Substrate-Competitive Manner.

Guangping DongYouchao DengAdam YasgarRavi YadavDaniel TalleyAlexey V ZakharovSankalp JainGanesha RaiNicholas NoinajAnton SimeonovRong Huang
Published in: Journal of medicinal chemistry (2022)
Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC 50 = 0.42 μM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC 50 = 0.5 μM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations.
Keyphrases
  • amino acid
  • protein protein
  • small molecule
  • binding protein
  • oxidative stress
  • genome wide
  • single cell
  • single molecule
  • cell proliferation
  • high resolution
  • structural basis