Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
- Lomonosov Moscow State Univ., Moscow (Russian Federation); Skolkovo Institute of Science and Technology (Russia)
- Univ. of Illinois, Chicago, IL (United States)
- Lomonosov Moscow State Univ., Moscow (Russian Federation)
- Petersburg Nuclear Physics Institute (Russia)
- Interbioscreen Ltd., Chernogolovka (Russia)
- Petersburg Nuclear Physics Institute (Russia); Interbioscreen Ltd, Chernogolovka (Russia)
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 Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- Grant/Contract Number:
- AC02- 06CH11357
- OSTI ID:
- 1373788
- Journal Information:
- Nucleic Acids Research, Vol. 45, Issue 12; ISSN 0305-1048
- Publisher:
- Oxford University PressCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
Similar Records
Peptidyl-CCA deacylation on the ribosome promoted by induced fit and the O3′-hydroxyl group of A76 of the unacylated A-site tRNA
The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics