Structures of the orthosomycin antibiotics avilamycin and evernimicin in complex with the bacterial 70S ribosome
Autor: | Paul Huter, Daniel N. Wilson, Scott C. Blanchard, Stefan Arenz, Fabian Nguyen, Manuel F. Juette, Michael Graf, Yury S. Polikanov |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Molecular Sequence Data 030106 microbiology Peptide Chain Elongation Translational Oligosaccharides Ribosome Subunits Large Bacterial Biology Ribosome 03 medical and health sciences Ribosomal protein 23S ribosomal RNA Large ribosomal subunit Escherichia coli Protein biosynthesis Amino Acid Sequence Binding site Binding Sites Multidisciplinary Molecular Structure Cryoelectron Microscopy Biological Sciences Ribosomal RNA Single Molecule Imaging Anti-Bacterial Agents Aminoglycosides 030104 developmental biology Biochemistry Transfer RNA |
Zdroj: | Proceedings of the National Academy of Sciences. 113:7527-7532 |
ISSN: | 1091-6490 0027-8424 |
DOI: | 10.1073/pnas.1604790113 |
Popis: | The ribosome is one of the major targets for therapeutic antibiotics; however, the rise in multidrug resistance is a growing threat to the utility of our current arsenal. The orthosomycin antibiotics evernimicin (EVN) and avilamycin (AVI) target the ribosome and do not display cross-resistance with any other classes of antibiotics, suggesting that they bind to a unique site on the ribosome and may therefore represent an avenue for development of new antimicrobial agents. Here we present cryo-EM structures of EVN and AVI in complex with the Escherichia coli ribosome at 3.6- to 3.9-Å resolution. The structures reveal that EVN and AVI bind to a single site on the large subunit that is distinct from other known antibiotic binding sites on the ribosome. Both antibiotics adopt an extended conformation spanning the minor grooves of helices 89 and 91 of the 23S rRNA and interacting with arginine residues of ribosomal protein L16. This binding site overlaps with the elbow region of A-site bound tRNA. Consistent with this finding, single-molecule FRET (smFRET) experiments show that both antibiotics interfere with late steps in the accommodation process, wherein aminoacyl-tRNA enters the peptidyltransferase center of the large ribosomal subunit. These data provide a structural and mechanistic rationale for how these antibiotics inhibit the elongation phase of protein synthesis. |
Databáze: | OpenAIRE |
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