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Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499580/ https://www.ncbi.nlm.nih.gov/pubmed/28505372 http://dx.doi.org/10.1093/nar/gkx413 |
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author | Osterman, Ilya A. Khabibullina, Nelli F. Komarova, Ekaterina S. Kasatsky, Pavel Kartsev, Victor G. Bogdanov, Alexey A. Dontsova, Olga A. Konevega, Andrey L. Sergiev, Petr V. Polikanov, Yury S. |
author_facet | Osterman, Ilya A. Khabibullina, Nelli F. Komarova, Ekaterina S. Kasatsky, Pavel Kartsev, Victor G. Bogdanov, Alexey A. Dontsova, Olga A. Konevega, Andrey L. Sergiev, Petr V. Polikanov, Yury S. |
author_sort | Osterman, Ilya A. |
collection | PubMed |
description | The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome. |
format | Online Article Text |
id | pubmed-5499580 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54995802017-07-10 Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state Osterman, Ilya A. Khabibullina, Nelli F. Komarova, Ekaterina S. Kasatsky, Pavel Kartsev, Victor G. Bogdanov, Alexey A. Dontsova, Olga A. Konevega, Andrey L. Sergiev, Petr V. Polikanov, Yury S. Nucleic Acids Res Structural Biology The emergence of multi-drug resistant bacteria is limiting the effectiveness of commonly used antibiotics, which spurs a renewed interest in revisiting older and poorly studied drugs. Streptogramins A is a class of protein synthesis inhibitors that target the peptidyl transferase center (PTC) on the large subunit of the ribosome. In this work, we have revealed the mode of action of the PTC inhibitor madumycin II, an alanine-containing streptogramin A antibiotic, in the context of a functional 70S ribosome containing tRNA substrates. Madumycin II inhibits the ribosome prior to the first cycle of peptide bond formation. It allows binding of the tRNAs to the ribosomal A and P sites, but prevents correct positioning of their CCA-ends into the PTC thus making peptide bond formation impossible. We also revealed a previously unseen drug-induced rearrangement of nucleotides U2506 and U2585 of the 23S rRNA resulting in the formation of the U2506•G2583 wobble pair that was attributed to a catalytically inactive state of the PTC. The structural and biochemical data reported here expand our knowledge on the fundamental mechanisms by which peptidyl transferase inhibitors modulate the catalytic activity of the ribosome. Oxford University Press 2017-07-07 2017-05-13 /pmc/articles/PMC5499580/ /pubmed/28505372 http://dx.doi.org/10.1093/nar/gkx413 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Structural Biology Osterman, Ilya A. Khabibullina, Nelli F. Komarova, Ekaterina S. Kasatsky, Pavel Kartsev, Victor G. Bogdanov, Alexey A. Dontsova, Olga A. Konevega, Andrey L. Sergiev, Petr V. Polikanov, Yury S. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title | Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title_full | Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title_fullStr | Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title_full_unstemmed | Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title_short | Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
title_sort | madumycin ii inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499580/ https://www.ncbi.nlm.nih.gov/pubmed/28505372 http://dx.doi.org/10.1093/nar/gkx413 |
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