The translation inhibitors kasugamycin, edeine and GE81112 target distinct steps during 30S initiation complex formation

Haaris A. Safdari, Martino Morici, Ana Sanchez-Castro, Andrea Dallapè, Helge Paternoga, Anna Maria Giuliodori, Attilio Fabbretti, Pohl Milón () and Daniel N. Wilson ()
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Haaris A. Safdari: University of Hamburg
Martino Morici: University of Hamburg
Ana Sanchez-Castro: Universidad Peruana de Ciencias Aplicadas (UPC)
Andrea Dallapè: University of Hamburg
Helge Paternoga: University of Hamburg
Anna Maria Giuliodori: University of Camerino
Attilio Fabbretti: University of Camerino
Pohl Milón: Universidad Peruana de Ciencias Aplicadas (UPC)
Daniel N. Wilson: University of Hamburg

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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 a unique manner.

Date: 2025
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DOI: 10.1038/s41467-025-57731-8

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