The 2.2 A 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 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.
Schluckebier
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Abbott Laboratories, D46Y-AP 10, 100 Abbott Park Road, Abbott Park, IL, 60064, USA. gerd.schluckebier@abbott.com
Zhong
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P
Stewart
K D
KD
Kavanaugh
T J
TJ
Abad-Zapatero
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C
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000378:metabolism; D001412:Bacillus subtilis / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial; D008024:Ligands; D008780:Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012338:RNA, Ribosomal, 23S / Q000096:biosynthesis / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
D000935:Antifungal Agents; D008024:Ligands; D012338:RNA, Ribosomal, 23S; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase; D000241:Adenosine; C006235:sinefungin