The 2.2 Å Structure of the rRNA Methyltransferase ErmC′ and its Complexes with Cofactor and Cofactor Analogs: Implications for the Reaction Mechanism

Author： Schluckebier G. Zhong P. Stewart K.D. Kavanaugh T.J. Abad-Zapatero C.

Publisher： Academic Press

ISSN： 0022-2836

Source： Journal of Molecular Biology, Vol.289, Iss.2, 1999-06, pp. : 277-291

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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.