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  Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics

Beckert, B., Leroy, E. C., Sothiselvam, S., Bock, L. V., Svetlov, M. S., Graf, M., et al. (2021). Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics. Nature Communications, 12: 4466. doi:10.1038/s41467-021-24674-9.

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 Creators:
Beckert, B., Author
Leroy, E. C., Author
Sothiselvam, S., Author
Bock, L. V.1, Author              
Svetlov, M. S., Author
Graf, M., Author
Arenz, S., Author
Abdelshahid, M., Author
Seip, B., Author
Grubmüller, H.1, Author              
Mankin, A. S., Author
Innis, C. A., Author
Vàzquez-Laslop, N., Author
Wilson, D. N., Author
Affiliations:
1Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578631              

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Free keywords: Antibiotics; Cryoelectron microscopy; Ribosome
 Abstract: Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.

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Language(s): eng - English
 Dates: 2021-07-22
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-021-24674-9
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Title: Nature Communications
Source Genre: Journal
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Pages: 15 Volume / Issue: 12 Sequence Number: 4466 Start / End Page: - Identifier: -