Open Access
Nucleic Acids Research, volume 45, issue 12, pages 7507-7514
Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
Osterman Ilya A
1, 2
,
Kasatsky Pavel
5
,
Kartsev Victor G.
6
,
Bogdanov Alexey A.
7
,
Dontsova Olga A.
1, 2
,
Konevega Andrey L.
8, 9
,
Sergiev Petr V.
1, 2
,
3
Dept. of Biological Sciences, Univ. of Illinois at Chicago, Chicago, IL 60607, USA.
|
5
6
Interbioscreen Ltd, Chernogolovka, Moscow Region 142432, Russia.
|
8
10
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607 USA.
|
Publication type: Journal Article
Publication date: 2017-05-13
Journal:
Nucleic Acids Research
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 14.9
ISSN: 03051048, 13624962
PubMed ID:
28505372
Genetics
Abstract
Abstract 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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Osterman I. A. et al. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state // Nucleic Acids Research. 2017. Vol. 45. No. 12. pp. 7507-7514.
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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. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state // Nucleic Acids Research. 2017. Vol. 45. No. 12. pp. 7507-7514.
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TY - JOUR
DO - 10.1093/nar/gkx413
UR - https://doi.org/10.1093%2Fnar%2Fgkx413
TI - Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
T2 - Nucleic Acids Research
AU - Kartsev, Victor G.
AU - Dontsova, Olga A.
AU - Polikanov, Yury S
AU - Osterman, Ilya A
AU - Khabibullina, Nelli F
AU - Komarova, Ekaterina S
AU - Kasatsky, Pavel
AU - Bogdanov, Alexey A.
AU - Konevega, Andrey L.
AU - Sergiev, Petr V.
PY - 2017
DA - 2017/05/13 00:00:00
PB - Oxford University Press
SP - 7507-7514
IS - 12
VL - 45
PMID - 28505372
SN - 0305-1048
SN - 1362-4962
ER -
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@article{2017_Osterman,
author = {Victor G. Kartsev and Olga A. Dontsova and Yury S Polikanov and Ilya A Osterman and Nelli F Khabibullina and Ekaterina S Komarova and Pavel Kasatsky and Alexey A. Bogdanov and Andrey L. Konevega and Petr V. Sergiev},
title = {Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state},
journal = {Nucleic Acids Research},
year = {2017},
volume = {45},
publisher = {Oxford University Press},
month = {may},
url = {https://doi.org/10.1093%2Fnar%2Fgkx413},
number = {12},
pages = {7507--7514},
doi = {10.1093/nar/gkx413}
}
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MLA
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Osterman, Ilya A., et al. “Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state.” Nucleic Acids Research, vol. 45, no. 12, May. 2017, pp. 7507-7514. https://doi.org/10.1093%2Fnar%2Fgkx413.