Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Context-based sensing of orthosomycin antibiotics by the translating ribosome

Mangano, Kyle ; Marks, James ; Klepacki, Dorota ; Saha, Chayan Kumar LU orcid ; Atkinson, Gemma C. LU ; Vázquez-Laslop, Nora and Mankin, Alexander S. (2022) In Nature Chemical Biology 18(11). p.1277-1286
Abstract

Orthosomycin antibiotics inhibit protein synthesis by binding to the large ribosomal subunit in the tRNA accommodation corridor, which is traversed by incoming aminoacyl-tRNAs. Structural and biochemical studies suggested that orthosomycins block accommodation of any aminoacyl-tRNAs in the ribosomal A-site. However, the mode of action of orthosomycins in vivo remained unknown. Here, by carrying out genome-wide analysis of antibiotic action in bacterial cells, we discovered that orthosomycins primarily inhibit the ribosomes engaged in translation of specific amino acid sequences. Our results reveal that the predominant sites of orthosomycin-induced translation arrest are defined by the nature of the incoming aminoacyl-tRNA and likely by... (More)

Orthosomycin antibiotics inhibit protein synthesis by binding to the large ribosomal subunit in the tRNA accommodation corridor, which is traversed by incoming aminoacyl-tRNAs. Structural and biochemical studies suggested that orthosomycins block accommodation of any aminoacyl-tRNAs in the ribosomal A-site. However, the mode of action of orthosomycins in vivo remained unknown. Here, by carrying out genome-wide analysis of antibiotic action in bacterial cells, we discovered that orthosomycins primarily inhibit the ribosomes engaged in translation of specific amino acid sequences. Our results reveal that the predominant sites of orthosomycin-induced translation arrest are defined by the nature of the incoming aminoacyl-tRNA and likely by the identity of the two C-terminal amino acid residues of the nascent protein. We show that nature exploits this antibiotic-sensing mechanism for directing programmed ribosome stalling within the regulatory open reading frame, which may control expression of an orthosomycin-resistance gene in a variety of bacterial species.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Chemical Biology
volume
18
issue
11
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:36138139
  • scopus:85138531265
ISSN
1552-4450
DOI
10.1038/s41589-022-01138-9
language
English
LU publication?
yes
id
4d833ebc-808e-4ba5-8965-815e7124a1bf
date added to LUP
2022-12-20 16:09:20
date last changed
2024-06-13 23:57:07
@article{4d833ebc-808e-4ba5-8965-815e7124a1bf,
  abstract     = {{<p>Orthosomycin antibiotics inhibit protein synthesis by binding to the large ribosomal subunit in the tRNA accommodation corridor, which is traversed by incoming aminoacyl-tRNAs. Structural and biochemical studies suggested that orthosomycins block accommodation of any aminoacyl-tRNAs in the ribosomal A-site. However, the mode of action of orthosomycins in vivo remained unknown. Here, by carrying out genome-wide analysis of antibiotic action in bacterial cells, we discovered that orthosomycins primarily inhibit the ribosomes engaged in translation of specific amino acid sequences. Our results reveal that the predominant sites of orthosomycin-induced translation arrest are defined by the nature of the incoming aminoacyl-tRNA and likely by the identity of the two C-terminal amino acid residues of the nascent protein. We show that nature exploits this antibiotic-sensing mechanism for directing programmed ribosome stalling within the regulatory open reading frame, which may control expression of an orthosomycin-resistance gene in a variety of bacterial species. <br/></p>}},
  author       = {{Mangano, Kyle and Marks, James and Klepacki, Dorota and Saha, Chayan Kumar and Atkinson, Gemma C. and Vázquez-Laslop, Nora and Mankin, Alexander S.}},
  issn         = {{1552-4450}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1277--1286}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Chemical Biology}},
  title        = {{Context-based sensing of orthosomycin antibiotics by the translating ribosome}},
  url          = {{http://dx.doi.org/10.1038/s41589-022-01138-9}},
  doi          = {{10.1038/s41589-022-01138-9}},
  volume       = {{18}},
  year         = {{2022}},
}