biostudies-literatureRamirez-Cardenas JMinisterio de Ciencia, Innovaci?n y UniversidadesDepartamento de Educaci?n, Cultura y Deporte, Gobierno de Arag?nUK Research and Innovation1279-1288https://www.ebi.ac.uk/biostudies/studies/S-EPMC11937963biostudies-literatureUnknown5(3)Enteropathogenic arginine-glycosyltransferases (Arg-GTs) alter higher eukaryotic proteins by attaching a GlcNAc residue to arginine acceptor sites, disrupting essential pathways such as NF-κB signaling, which promotes bacterial survival. These enzymes are potential drug targets for treating related diseases. In this study, we present a novel STD NMR Epitope Perturbation by Mutation spectroscopic approach that, in combination with hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations, shows that the highly potent broad-spectrum anticancer drug YM155 serves as a potential noncompetitive inhibitor of these enzymes. It induces a conformation of the arginine acceptor site unfavorable for GlcNAc transfer, which underlies the molecular mechanism by which this JACS AuSTD NMR Epitope Perturbation by Mutation Unveils the Mechanism of YM155 as an Arginine-Glycosyltransferases Inhibitor Effective in Treating Enteropathogenic Diseases.PMC11937963E34_R17PID2022-142879NB-I00MR/V02213X/1LMP58_18PID2022-136362NB-100Taleb VHurtado-Guerrero RAngulo JZhu CRamirez-Cardenas JZhang YMunoz-Garcia JCStruwe WBCalvaresi VHasan KHardwidge PREl Qaidi SVeloz BfalseSTD NMR Epitope Perturbation by Mutation Unveils the Mechanism of YM155 as an Arginine-Glycosyltransferases Inhibitor Effective in Treating Enteropathogenic Diseases.Enteropathogenic arginine-glycosyltransferases (Arg-GTs) alter higher eukaryotic proteins by attaching a GlcNAc residue to arginine acceptor sites, disrupting essential pathways such as NF-κB signaling, which promotes bacterial survival. These enzymes are potential drug targets for treating related diseases. In this study, we present a novel STD NMR Epitope Perturbation by Mutation spectroscopic approach that, in combination with hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations, shows that the highly potent broad-spectrum anticancer drug YM155 serves as a potential noncompetitive inhibitor of these enzymes. It induces a conformation of the arginine acceptor site unfavorable for GlcNAc transfer, which underlies the molecular mechanism by which this 2025-01-01T00:00:00Z2025 Mar2026-06-02T21:12:25.557Z2026-05-29T03:06:27.953ZS-EPMC119379634015124310.1021/jacsau.4c01140