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Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
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Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
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Journal Article
Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
2023
Overview
Thermorubin (THB) is a long-known broad-spectrum ribosome-targeting antibiotic, but the molecular mechanism of its action was unclear. Here, our precise fast-kinetics assays in a reconstituted
Escherichia coli
translation system and 1.96 Å resolution cryo-EM structure of THB-bound 70S ribosome with mRNA and initiator tRNA, independently suggest that THB binding at the intersubunit bridge B2a near decoding center of the ribosome interferes with the binding of A-site substrates aminoacyl-tRNAs and class-I release factors, thereby inhibiting elongation and termination steps of bacterial translation. Furthermore, THB acts as an anti-dissociation agent that tethers the ribosomal subunits and blocks ribosome recycling, subsequently reducing the pool of active ribosomes. Our results show that THB does not inhibit translation initiation as proposed earlier and provide a complete mechanism of how THB perturbs bacterial protein synthesis. This in-depth characterization will hopefully spur efforts toward the design of THB analogs with improved solubility and effectivity against multidrug-resistant bacteria.
Thermorubin is a ribosome-targeting antibiotic. Here, using fast-kinetics and cryoEM, the authors reveal that thermorubin primarily blocks ribosome-recycling by tethering the ribosomal subunits besides impeding translation elongation and termination steps.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/16
/ 82/80
/ 82/83
/ Anti-Bacterial Agents - pharmacology
/ Bacteria
/ Binding
/ Biokemi
/ Biologi med inriktning mot molekylärbiologi
/ Biologi med inriktning mot strukturbiologi
/ Biology with specialization in Molecular Biology
/ Biology with specialization in Structural Biology
/ E coli
/ Humanities and Social Sciences
/ Kinetics
/ mRNA
/ Proteins
/ Ribosome
/ Science
/ Tethers
/ tRNA
