Paenilamicins are context-specific translocation inhibitors of protein synthesis.

Autor: Koller TO; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Berger MJ; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Morici M; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Paternoga H; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Bulatov T; Institut für Chemie, Technische Universität Berlin, Berlin, Germany., Di Stasi A; Department of Life Sciences, University of Trieste, Trieste, Italy., Dang T; Institut für Chemie, Technische Universität Berlin, Berlin, Germany., Mainz A; Institut für Chemie, Technische Universität Berlin, Berlin, Germany., Raulf K; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Crowe-McAuliffe C; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany., Scocchi M; Department of Life Sciences, University of Trieste, Trieste, Italy., Mardirossian M; Department of Life Sciences, University of Trieste, Trieste, Italy., Beckert B; Dubochet Center for Imaging (DCI) at EPFL, EPFL SB IPHYS DCI, Lausanne, Switzerland., Vázquez-Laslop N; Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA.; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA., Mankin AS; Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA.; Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA., Süssmuth RD; Institut für Chemie, Technische Universität Berlin, Berlin, Germany., Wilson DN; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany. Daniel.Wilson@chemie.uni-hamburg.de.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2024 Dec; Vol. 20 (12), pp. 1691-1700. Date of Electronic Publication: 2024 Oct 17.
DOI: 10.1038/s41589-024-01752-9
Abstrakt: The paenilamicins are a group of hybrid nonribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here we determine structures of paenilamicin PamB2-stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site transfer RNAs (tRNAs). In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms used by P. larvae. We further demonstrate that PamB2 interferes with the translocation of messenger RNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a class of context-specific translocation inhibitors.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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