A binding site for the antibiotic GE81112 in the ribosomal mRNA channel

This study uses high-resolution cryo-electron microscopy (cryo-EM) to reveal the precise binding site of the antibiotic GE81112 on the bacterial ribosome's 30S subunit. GE81112 targets the initiation phase of bacterial protein synthesis, specifically interacting within the mRNA channel, distant from the initiation factor and initiator tRNA-binding sites. This indicates that GE81112 acts allosterically, disrupting and preventing conformational rearrangements in IF3 and the proper positioning of the initiator tRNA, stalling the ribosome in an unlocked pre-initiation complex. The findings identify key ribosomal interactions, including conserved nucleotides in helices 23, 24, and 45, and protein S11, highlighting GE81112's unique binding mode among initiation inhibitors. This structural characterization enhances our understanding of antibiotic interference with translation initiation and provides insights to support rational design strategies for improved GE81112 derivatives.

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Publication Details

Journal
mBio
Published
2025-10-24
DOI
https://doi.org/10.1128/mbio.03978-24
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
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article

A binding site for the antibiotic GE81112 in the ribosomal mRNA channel

Letizia Brandi, Andreas Schedlbauer, Sean R. Connell, Tatsuya Kaminishi et al.
mBio
RNA and protein synthesis mechanisms
article

A binding site for the antibiotic GE81112 in the ribosomal mRNA channel

Letizia Brandi, Andreas Schedlbauer, Sean R. Connell, Tatsuya Kaminishi, Retina Çapuni, Kristina Barragán Sanz, Paola Fucini, Idoia Iturrioz, Jorge P. López‐Alonso, David Gil‐Carton, Claudio O. Gualerzi, Ronny Zegarra-Peña, Wouter van Bakel, Xu Han, Ransford Parry, Borja Ochoa-Lizarralde
article en

Abstract

This study uses high-resolution cryo-electron microscopy (cryo-EM) to reveal the precise binding site of the antibiotic GE81112 on the bacterial ribosome's 30S subunit. GE81112 targets the initiation phase of bacterial protein synthesis, specifically interacting within the mRNA channel, distant from the initiation factor and initiator tRNA-binding sites. This indicates that GE81112 acts allosterically, disrupting and preventing conformational rearrangements in IF3 and the proper positioning of the initiator tRNA, stalling the ribosome in an unlocked pre-initiation complex. The findings identify key ribosomal interactions, including conserved nucleotides in helices 23, 24, and 45, and protein S11, highlighting GE81112's unique binding mode among initiation inhibitors. This structural characterization enhances our understanding of antibiotic interference with translation initiation and provides insights to support rational design strategies for improved GE81112 derivatives.

mBioVol. 16(11)
Ikerbasque (ES), Università di Camerino (IT), University of Medicine Tirana (AL), University of Balamand (LB), University of the Basque Country (ES), BioCruces Health research Institute (ES), Basque Centre for Climate Change (ES), CIC bioGUNE (ES), Instituto Biofisika (ES), Austrian Centre for Electron Microscopy and Nanoanalysis (AT), The University of Osaka (JP)
Openalex Percentile: Top 73%
RNA and protein synthesis mechanisms
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