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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 918Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
Antibiotic, Thermorubin, Ribosome, Translation inhibition, Subunit tethering
National Category
Biochemistry Molecular Biology Structural Biology
Research subject
Biochemistry; Biology with specialization in Molecular Biology; Biology with specialization in Structural Biology
Identifiers
urn:nbn:se:uu:diva-486747 (URN)10.1038/s41467-023-36528-7 (DOI)001001567400001 ()36806263 (PubMedID)
Funder
Uppsala University
2022-10-192022-10-192025-02-20Bibliographically approved