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Fusidic acid targets elongation factor G in several stages of translocation on the bacterial ribosome

Borg, Anneli ; Holm, Mikael ; Shiroyama, Ikue ; Hauryliuk, Vasili LU orcid ; Pavlov, Michael ; Sanyal, Suparna LU and Ehrenberg, Måns (2015) In Journal of Biological Chemistry 290(6). p.3440-3454
Abstract

The antibiotic fusidic acid (FA) targets elongation factor G (EF-G) and inhibits ribosomal peptide elongation and ribosome recycling, but deeper mechanistic aspects of FA action have remained unknown. Using quench flow and stopped flow experiments in a biochemical system for protein synthesis and taking advantage of separate time scales for inhibited (10 s) and uninhibited (100 ms) elongation cycles, a detailed kinetic model of FA action was obtained. FA targets EF-G at an early stage in the translocation process (I), which proceeds unhindered by the presence of the drug to a later stage (II), where the ribosome stalls. Stalling may also occur at a third stage of translocation (III), just before release of EF-G from the... (More)

The antibiotic fusidic acid (FA) targets elongation factor G (EF-G) and inhibits ribosomal peptide elongation and ribosome recycling, but deeper mechanistic aspects of FA action have remained unknown. Using quench flow and stopped flow experiments in a biochemical system for protein synthesis and taking advantage of separate time scales for inhibited (10 s) and uninhibited (100 ms) elongation cycles, a detailed kinetic model of FA action was obtained. FA targets EF-G at an early stage in the translocation process (I), which proceeds unhindered by the presence of the drug to a later stage (II), where the ribosome stalls. Stalling may also occur at a third stage of translocation (III), just before release of EF-G from the post-translocation ribosome. We show that FA is a strong elongation inhibitor (K50% ≈ 1 μM), discuss the identity of the FA targeted states, and place existing cryo-EM and crystal structures in their functional context.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
290
issue
6
pages
15 pages
publisher
American Society for Biochemistry and Molecular Biology
external identifiers
  • pmid:25451927
  • scopus:84922373723
ISSN
0021-9258
DOI
10.1074/jbc.M114.611608
language
English
LU publication?
no
additional info
Publisher Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.
id
e6236a11-1185-4f9e-b44e-6fa8a8f4a10a
date added to LUP
2021-09-24 20:43:30
date last changed
2024-04-06 08:45:35
@article{e6236a11-1185-4f9e-b44e-6fa8a8f4a10a,
  abstract     = {{<p>The antibiotic fusidic acid (FA) targets elongation factor G (EF-G) and inhibits ribosomal peptide elongation and ribosome recycling, but deeper mechanistic aspects of FA action have remained unknown. Using quench flow and stopped flow experiments in a biochemical system for protein synthesis and taking advantage of separate time scales for inhibited (10 s) and uninhibited (100 ms) elongation cycles, a detailed kinetic model of FA action was obtained. FA targets EF-G at an early stage in the translocation process (I), which proceeds unhindered by the presence of the drug to a later stage (II), where the ribosome stalls. Stalling may also occur at a third stage of translocation (III), just before release of EF-G from the post-translocation ribosome. We show that FA is a strong elongation inhibitor (K<sub>50%</sub> ≈ 1 μM), discuss the identity of the FA targeted states, and place existing cryo-EM and crystal structures in their functional context.</p>}},
  author       = {{Borg, Anneli and Holm, Mikael and Shiroyama, Ikue and Hauryliuk, Vasili and Pavlov, Michael and Sanyal, Suparna and Ehrenberg, Måns}},
  issn         = {{0021-9258}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{6}},
  pages        = {{3440--3454}},
  publisher    = {{American Society for Biochemistry and Molecular Biology}},
  series       = {{Journal of Biological Chemistry}},
  title        = {{Fusidic acid targets elongation factor G in several stages of translocation on the bacterial ribosome}},
  url          = {{http://dx.doi.org/10.1074/jbc.M114.611608}},
  doi          = {{10.1074/jbc.M114.611608}},
  volume       = {{290}},
  year         = {{2015}},
}