Proceedings of the National Academy of Sciences - PNAS, 2014-04, Vol.111 (17), p.6275-6280
2014
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Details
- Autor(en) / Beteiligte
- Titel
- Molecular recognition and modification of the 30S ribosome by the aminoglycoside-resistance methyltransferase NpmA
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2014-04, Vol.111 (17), p.6275-6280
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Aminoglycosides are potent, broad spectrum, ribosome-targeting antibacterials whose clinical efficacy is seriously threatened by multiple resistance mechanisms. Here, we report the structural basis for 30S recognition by the novel plasmid-mediated aminoglycoside-resistance rRNA methyltransferase A (NpmA). These studies are supported by biochemical and functional assays that define the molecular features necessary for NpmA to catalyze m ¹A1408 modification and confer resistance. The requirement for the mature 30S as a substrate for NpmA is clearly explained by its recognition of four disparate 16S rRNA helices brought into proximity by 30S assembly. Our structure captures a “precatalytic state” in which multiple structural reorganizations orient functionally critical residues to flip A1408 from helix 44 and position it precisely in a remodeled active site for methylation. Our findings provide a new molecular framework for the activity of aminoglycoside-resistance rRNA methyltransferases that may serve as a functional paradigm for other modification enzymes acting late in 30S biogenesis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1402789111Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4035980
- Format
- –
- Schlagworte
- Active sites, Adenosine - analogs & derivatives, Adenosine - chemistry, Adenosine - pharmacology, Amino Acids - metabolism, Aminoglycosides, Aminoglycosides - pharmacology, Antibiotics, Biocatalysis - drug effects, Biological Sciences, Biosynthesis, Catalysis, Catalytic Domain, Conserved Sequence, Crystallography, X-Ray, Drug Resistance, Bacterial - drug effects, Electrostatics, Enzymes, Escherichia coli - drug effects, Escherichia coli - enzymology, Escherichia coli Proteins - chemistry, Escherichia coli Proteins - metabolism, Gene Transfer, Horizontal - drug effects, Methylation - drug effects, Methyltransferases - chemistry, Methyltransferases - metabolism, Models, Molecular, Nucleotides, Nucleotides - metabolism, Phosphates, Plasmids, Protein Structure, Secondary, Protein Structure, Tertiary, Ribonucleic acid, Ribosome Subunits, Small, Bacterial - chemistry, Ribosome Subunits, Small, Bacterial - metabolism, Ribosomes, RNA, RNA, Ribosomal, 16S - chemistry, Structure-Activity Relationship, Substrates