Madumycin II inhibits peptide bond formation by forcing the peptidyl transferase center into an inactive state
| Autor: | Victor G Kartsev, Petr V. Sergiev, Ekaterina S. Komarova, Pavel Kasatsky, Andrey L. Konevega, Ilya A. Osterman, Olga A. Dontsova, Nelli F Khabibullina, Alexey A. Bogdanov, Yury S. Polikanov |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Streptogramins Models Molecular Peptidyl transferase 030106 microbiology Biology Ribosome 03 medical and health sciences Bacterial Proteins RNA Transfer 23S ribosomal RNA Structural Biology Catalytic Domain Genetics Escherichia coli Peptide bond Binding site Protein Synthesis Inhibitors Binding Sites Thermus thermophilus Ribosomal RNA 3. Good health Anti-Bacterial Agents RNA Ribosomal 23S 030104 developmental biology Biochemistry Protein Biosynthesis Transfer RNA Peptidyl Transferases biology.protein Nucleic Acid Conformation Ribosomes |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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