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

Journal Article · · Nucleic Acids Research
DOI:https://doi.org/10.1093/nar/gkx413· OSTI ID:1373788
 [1];  [2];  [3];  [4];  [5];  [3];  [1];  [6];  [1];  [2]
  1. Lomonosov Moscow State Univ., Moscow (Russian Federation); Skolkovo Institute of Science and Technology (Russia)
  2. Univ. of Illinois, Chicago, IL (United States)
  3. Lomonosov Moscow State Univ., Moscow (Russian Federation)
  4. Petersburg Nuclear Physics Institute (Russia)
  5. Interbioscreen Ltd., Chernogolovka (Russia)
  6. Petersburg Nuclear Physics Institute (Russia); Interbioscreen Ltd, Chernogolovka (Russia)
+ Show Author Affiliations
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.
Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1373788
Journal Information:
Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 12 Vol. 45; ISSN 0305-1048
Publisher:
Oxford University PressCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Cited By (6)

Structure of ribosome-bound azole-modified peptide phazolicin rationalizes its species-specific mode of bacterial translation inhibition journal October 2019
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High-resolution crystal structures of ribosome-bound chloramphenicol and erythromycin provide the ultimate basis for their competition journal February 2019
The Mechanisms of Action of Ribosome-Targeting Peptide Antibiotics journal May 2018
Identification of Novel Antibacterials Using Machine Learning Techniques journal August 2019
Pseudouridinylation of mRNA coding sequences alters translation journal October 2019

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