Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state

Osterman, I.A.; Khabibullina, N.F.; Komarova, E.S.; Kasatsky, P.; Kartsev, V.G.; Bogdanov, A.A.; Dontsova, O.A.; Konevega, A.L.; Sergiev, P.V.; Polikanov, Y.S.

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Web of Science, Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 3 декабря 2020 г.

Авторы: 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.
Журнал: Nucleic Acids Research
Год издания: 2017
Издательство: Oxford University Press
Местоположение издательства: United Kingdom
DOI: 10.1093/nar/gkx413
Аннотация: 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.
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Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive stateстатья

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