The 2.2 Å structure of the rRNA methyltransferase ErmC′ and its complexes with cofactor and cofactor analogs: implications for the reaction mechanism

Abstract

The rRNA methyltransferase ErmC′ transfers methyl groups from S-adenosyl- l-methionine to atom N6 of an adenine base within the peptidyltransferase loop of 23 S rRNA, thus conferring antibiotic resistance against a number of macrolide antibiotics. The crystal structures of ErmC′ and of its complexes with the cofactor S-adenosyl- l-methionine, the reaction product S-adenosyl- l-homocysteine and the methyltransferase inhibitor Sinefungin, respectively, show that the enzyme undergoes small conformational changes upon ligand binding. Overall, the ligand molecules bind to the protein in a similar mode as observed for other methyltransferases. Small differences between the binding of the amino acid parts of the different ligands are correlated with differences in their chemical structure. A model for the transition-state based on the atomic details of the active site is consistent with a one-step methyl-transfer mechanism and might serve as a first step towards the design of potent Erm inhibitors.