2. Academic Validation
  3. Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state

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

  • Nucleic Acids Res. 2017 Jul 7;45(12):7507-7514. doi: 10.1093/nar/gkx413.
Ilya A Osterman 1 2,  Nelli F Khabibullina 3,  Ekaterina S Komarova 4,  Pavel Kasatsky 5,  Victor G Kartsev 6,  Alexey A Bogdanov 1,  Olga A Dontsova 1 2,  Andrey L Konevega 5 7,  Petr V Sergiev 1 2,  Yury S Polikanov 3 8
Affiliations

Affiliations

  • 1 Lomonosov Moscow State University, Department of Chemistry and A.N. Belozersky Institute of Physico-Chemical Biology, Moscow 119992, Russia.
  • 2 Skolkovo Institute of Science and Technology, Skolkovo, Moscow region 143025, Russia.
  • 3 Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 4 Lomonosov Moscow State University, Department of Bioengineering and Bioinformatics, Moscow 119992, Russia.
  • 5 Petersburg Nuclear Physics Institute, NRC "Kurchatov Institute", Gatchina 188300, Russia.
  • 6 Interbioscreen Ltd, Chernogolovka, Moscow Region 142432, Russia.
  • 7 Peter the Great St.Petersburg Polytechnic University, Saint Petersburg, 195251, Russia.
  • 8 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60607, USA.
PMID: 28505372 DOI: 10.1093/nar/gkx413
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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