Paenilamicins are context-specific translocation inhibitors of protein synthesis
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.
Authors
- Daniel N. Wilson (ORCID: https://orcid.org/0000-0003-3816-3828)
- Caillan Crowe‐McAuliffe (ORCID: https://orcid.org/0000-0003-2157-4639)
- Timm O. Koller (ORCID: https://orcid.org/0000-0003-0145-4891)
- Martino Morici (ORCID: https://orcid.org/0000-0002-7304-5264)
- Tam Dang (ORCID: https://orcid.org/0000-0002-3602-1917)
- Alexander S. Mankin (ORCID: https://orcid.org/0000-0002-3301-827X)
- Helge Paternoga (ORCID: https://orcid.org/0000-0001-8335-3239)
- Roderich D. Süßmuth (ORCID: https://orcid.org/0000-0001-7027-2069)
- Andi Mainz (ORCID: https://orcid.org/0000-0003-3428-864X)
- Max Berger (ORCID: https://orcid.org/0009-0001-7093-9086)
- Timur M. Bulatov (ORCID: https://orcid.org/0000-0001-6989-7221)
- Marco Scocchi (ORCID: https://orcid.org/0000-0003-1247-3641)
- Nora Vázquez‐Laslop (ORCID: https://orcid.org/0000-0003-2256-693X)
- Mario Mardirossian (ORCID: https://orcid.org/0000-0001-5735-2363)
- Adriana Di Stasi
- Bertrand Beckert (ORCID: https://orcid.org/0000-0002-9507-3127)
- Karoline Raulf
Institutions
- University of Trieste (IT)
- Universität Hamburg (DE)
- University of Illinois Chicago (US)
- Hamburg Institut (Germany) (DE)
- Technische Universität Berlin (DE)
- École Polytechnique Fédérale de Lausanne (CH)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1038/s41589-024-01752-9
- Citations
- 6
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Deutsche Forschungsgemeinschaft
- École Polytechnique Fédérale de Lausanne
- Universität Hamburg
- Université de Genève
- Université de Lausanne
- National Institutes of Health
- University of Illinois at Urbana-Champaign