Open Access
Proceedings of the National Academy of Sciences of the United States of America, volume 111, issue 27, pages 9804-9809
Macrolide antibiotics allosterically predispose the ribosome for translation arrest
Sothiselvam Shanmugapriya
1
,
Liu Bo
2
,
Han Wei
2
,
Ramu Haripriya
1
,
Klepacki Dorota
1
,
Atkinson Gemma Catherine
3, 4, 5
,
Brauer Age
6
,
Remm Maido
6
,
Tenson Tanel
3
,
Schulten Klaus
2
,
Vázquez Laslop Nora
1
,
Mankin Alexander S
1
1
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
|
2
Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
|
3
Institute of Technology, University of Tartu, 50411 Tartu, Estonia;
|
4
Department of Molecular Biology and
6
Institute of Molecular and Cell Biology, University of Tartu, 50411 Tartu, Estonia
|
Publication type: Journal Article
Publication date: 2014-06-24
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11.1
ISSN: 00278424, 10916490
PubMed ID:
24961372
Multidisciplinary
Abstract
Significance Translation arrest regulated by nascent peptides and small cofactors controls expression of important genes, including medically relevant macrolide antibiotic resistance genes. The role of the cofactor for triggering this mechanism has remained enigmatic. Previous studies suggested that extensive interactions between the nascent chain and the antibiotic molecule juxtaposed in the ribosomal exit tunnel were critical for halting translation. However, here we show that the antibiotic induces stalling, even without significant contacts with the peptide, by allosterically altering the peptidyl transferase center. This finding unveils a previously unknown role of cofactors for translation arrest and demonstrates the existence of a functional link between the exit tunnel and the catalytic center of the ribosome. 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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Sothiselvam S. et al. Macrolide antibiotics allosterically predispose the ribosome for translation arrest // Proceedings of the National Academy of Sciences of the United States of America. 2014. Vol. 111. No. 27. pp. 9804-9809.
GOST all authors (up to 50)
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Sothiselvam S., Liu B., Han W., Ramu H., Klepacki D., Atkinson G. C., Brauer A., Remm M., Tenson T., Schulten K., Vázquez Laslop N., Mankin A. S. Macrolide antibiotics allosterically predispose the ribosome for translation arrest // Proceedings of the National Academy of Sciences of the United States of America. 2014. Vol. 111. No. 27. pp. 9804-9809.
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RIS
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TY - JOUR
DO - 10.1073/pnas.1403586111
UR - https://doi.org/10.1073%2Fpnas.1403586111
TI - Macrolide antibiotics allosterically predispose the ribosome for translation arrest
T2 - Proceedings of the National Academy of Sciences of the United States of America
AU - Sothiselvam, Shanmugapriya
AU - Liu, Bo
AU - Han, Wei
AU - Ramu, Haripriya
AU - Klepacki, Dorota
AU - Atkinson, Gemma Catherine
AU - Brauer, Age
AU - Remm, Maido
AU - Tenson, Tanel
AU - Schulten, Klaus
AU - Vázquez Laslop, Nora
AU - Mankin, Alexander S
PY - 2014
DA - 2014/06/24 00:00:00
PB - Proceedings of the National Academy of Sciences (PNAS)
SP - 9804-9809
IS - 27
VL - 111
PMID - 24961372
SN - 0027-8424
SN - 1091-6490
ER -
Cite this
BibTex
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@article{2014_Sothiselvam,
author = {Shanmugapriya Sothiselvam and Bo Liu and Wei Han and Haripriya Ramu and Dorota Klepacki and Gemma Catherine Atkinson and Age Brauer and Maido Remm and Tanel Tenson and Klaus Schulten and Nora Vázquez Laslop and Alexander S Mankin},
title = {Macrolide antibiotics allosterically predispose the ribosome for translation arrest},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2014},
volume = {111},
publisher = {Proceedings of the National Academy of Sciences (PNAS)},
month = {jun},
url = {https://doi.org/10.1073%2Fpnas.1403586111},
number = {27},
pages = {9804--9809},
doi = {10.1073/pnas.1403586111}
}
Cite this
MLA
Copy
Sothiselvam, Shanmugapriya, et al. “Macrolide antibiotics allosterically predispose the ribosome for translation arrest.” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 27, Jun. 2014, pp. 9804-9809. https://doi.org/10.1073%2Fpnas.1403586111.