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The translation inhibitors kasugamycin, edeine and GE81112 target distinct steps during 30S initiation complex formation
Open accessPreprint — published as 10.1038/s41467-025-57731-8 · Paper page
Abstract
During bacterial translation initiation, the 30S ribosomal subunit, initiation factors, and initiator tRNA define the reading frame of the mRNA. This process is inhibited by kasugamycin, edeine and GE81112, however, their mechanisms of action have not been fully elucidated. Here we present cryo-electron microscopy structures of 30S initiation intermediate complexes formed in the presence of kasugamycin, edeine and GE81112 at resolutions of 2.0-2.9 Å. The structures reveal that all three antibiotics bind within the E-site of the 30S and preclude 30S initiation complex formation. While kasugamycin and edeine affect early steps of 30S pre-initiation complex formation, GE81112 stalls pre-initiation complex formation at a further step by allowing start codon recognition, but impeding IF3 departure. Collectively, our work highlights how chemically distinct compounds binding at a conserved site on the 30S can interfere with translation initiation in unique manner.
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Metadata
- Authors
- Safdari, H. A., Morici, M., Sanchez-Castro, A., Dallapè, A., Paternoga, H., Giuliodori, A. M., Fabbretti, A., Milón, P., & Wilson, D. N.
- Affiliations
- Universität Hamburg (DE)
- Peruvian University of Applied Sciences (PE)
- Università di Camerino (IT)
- Corresponding author
- Milón, Pohl
- Wilson, Daniel N.
- ORCID
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2024-09-27
- Volume
- 16
- Issue
- 1
- Pages
- 2470-2470
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11903750
- OpenAlex
- W4408360839
- Cited by
- 11
- References
- 1
- Citations by year
- 2026: 7 · 2025: 4
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (INST 152/772-1, 152/777 -1 FUGG, WI3285/12-1, 152/775-1, 152/774-1, 152/776-1)
- Universität Hamburg
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- translation initiation, 30S ribosomal subunit, kasugamycin, edeine, translation inhibitors, preinitiation complex, start codon recognition, cryo-EM structure, antibiotic mechanism of action
- MeSH terms
- Aminoglycosides, Anti-Bacterial Agents, Escherichia coli, Peptide Chain Initiation, Translational, Protein Synthesis Inhibitors, Protein Biosynthesis, Codon, Initiator, Cryoelectron Microscopy, Ribosome Subunits, Small, Bacterial
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