The 2.2 angstrom structure of the rRNA methyltransferase ErmC ' and its complexes with cofactor and cofactor analogs: Implications for the reaction mechanism

The rRNA methyltransferase ErmC' transfers methyl groups from S-adenosyl-L- methionine to atom N6 of an adenine base within the peptidyltransferase loo p of 23 S rRNA, thus conferring antibiotic resistance against a number of m acrolide 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 b inding. Overall, the ligand molecules bind to the protein in a similar mode as observed for other methyltransferases. Small differences between the bi nding of the amino acid parts of the different ligands are correlated with differences in their chemical structure. A model for the transition-state b ased 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 desi gn of potent Erm inhibitors. (C) 1999 Academic Press.