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Macrolide antibiotics allosterically predispose the ribosome for translation arrest

Sothiselvam, Shanmugapriya ; Liu, Bo ; Han, Wei ; Ramu, Haripriya ; Klepacki, Dorota ; Atkinson, Gemma Catherine LU ; Brauer, Age ; Remm, Maido ; Tenson, Tanel and Schulten, Klaus , et al. (2014) In Proceedings of the National Academy of Sciences of the United States of America 111(27). p.9804-9809
Abstract

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the... (More)

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

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publishing date
type
Contribution to journal
publication status
published
keywords
Allosteric Regulation, Anti-Bacterial Agents/pharmacology, Cell-Free System, Macrolides/pharmacology, Molecular Conformation, Molecular Dynamics Simulation, Protein Biosynthesis/drug effects, Ribosomes/drug effects
in
Proceedings of the National Academy of Sciences of the United States of America
volume
111
issue
27
pages
9804 - 9809
publisher
National Academy of Sciences
external identifiers
  • pmid:24961372
  • scopus:84904016052
ISSN
1091-6490
DOI
10.1073/pnas.1403586111
language
English
LU publication?
no
id
51d2a302-b7f5-4ab5-9e7b-5015aeb0e0eb
date added to LUP
2021-09-27 15:52:45
date last changed
2024-04-20 13:03:28
@article{51d2a302-b7f5-4ab5-9e7b-5015aeb0e0eb,
  abstract     = {{<p>Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome. </p>}},
  author       = {{Sothiselvam, Shanmugapriya and Liu, Bo and Han, Wei and Ramu, Haripriya and Klepacki, Dorota and Atkinson, Gemma Catherine and Brauer, Age and Remm, Maido and Tenson, Tanel and Schulten, Klaus and Vázquez-Laslop, Nora and Mankin, Alexander S}},
  issn         = {{1091-6490}},
  keywords     = {{Allosteric Regulation; Anti-Bacterial Agents/pharmacology; Cell-Free System; Macrolides/pharmacology; Molecular Conformation; Molecular Dynamics Simulation; Protein Biosynthesis/drug effects; Ribosomes/drug effects}},
  language     = {{eng}},
  number       = {{27}},
  pages        = {{9804--9809}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Macrolide antibiotics allosterically predispose the ribosome for translation arrest}},
  url          = {{http://dx.doi.org/10.1073/pnas.1403586111}},
  doi          = {{10.1073/pnas.1403586111}},
  volume       = {{111}},
  year         = {{2014}},
}