The 2.2 A structure of the rRNA methyltransferase ErmC' and its complexes with cofactor and cofactor analogs

Abbott Laboratories, D46Y-AP 10, 100 Abbott Park Road, Abbott Park, IL, 60064, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 07/1999; 289(2):277-91. DOI: 10.1006/jmbi.1999.2788
Source: PubMed


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.

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    • "Methyltransferases (MTases) transfer a methyl group from a donor to an acceptor, and catalyze a diverse range of substrates (small organic molecules, DNA, RNA, proteins, lipids) [27]. The rRNA MTase ErmC' methylates an adenine base in 23S rRNA, which confers resistance by obstructing the contact site for the antibiotics [28]. "
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    PLoS ONE 11/2012; 7(11):e49313. DOI:10.1371/journal.pone.0049313 · 3.23 Impact Factor
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    • "The crystal structure of Mtf1 showed that it consists of two domains, a large α/β N-terminal domain and a smaller tetra-α helical C-terminal domain separated by a cleft (20). Structurally the N-terminal domain was closely related to a series of rRNA methyltransferases (21–24). "
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    Nucleic Acids Research 02/2011; 39(12):5119-30. DOI:10.1093/nar/gkr103 · 9.11 Impact Factor
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    • "Because of uncertainties in the position of the S-adenosyl methionine (SAM) cofactor, this small molecule was not included during the refinement. Instead, the SAM moiety was transformed to adopt a binding mode similar to that in the ErmC′ structure (PDB entry: 1QAO8); full-atom refinement was performed under the Rosetta energy function augmented with restraints that preserved hydrogen bonding and packing interactions, analogous to those observed for ErmC′. The current unavailability of the crystallographic structure for T33 prevents us from assessing the accuracy of this small-molecule remodeling. "
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