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Amicoumacin A Inhibits Translation by Stabilizing mRNA Interaction with the Ribosome

Author:
Polikanov, Yury S., Osterman, Ilya A., Szal, Teresa, Tashlitsky, Vadim N., Serebryakova, Marina V., Kusochek, Pavel, Bulkley, David, Malanicheva, Irina A., Efimenko, Tatyana A., Efremenkova, Olga V., Konevega, Andrey L., Shaw, Karen J., Bogdanov, Alexey A., Rodnina, Marina V., Dontsova, Olga A., Mankin, Alexander S., Steitz, Thomas A., Sergiev, Petr V.
Source:
Molecular cell 2014 v.56 pp. 531-540
ISSN:
1097-2765
Subject:
antibiotics, binding sites, crystal structure, messenger RNA, mutation, nucleotides, protein subunits, protein synthesis inhibitors, ribosomal RNA, ribosomal proteins, ribosomes, translation (genetics)
Abstract:
We demonstrate that the antibiotic amicoumacin A (AMI) is a potent inhibitor of protein synthesis. Resistance mutations in helix 24 of the 16S rRNA mapped the AMI binding site to the small ribosomal subunit. The crystal structure of bacterial ribosome in complex with AMI solved at 2.4 Å resolution revealed that the antibiotic makes contacts with universally conserved nucleotides of 16S rRNA in the E site and the mRNA backbone. Simultaneous interactions of AMI with 16S rRNA and mRNA and the in vivo experimental evidence suggest that it may inhibit the progression of the ribosome along mRNA. Consistent with this proposal, binding of AMI interferes with translocation in vitro. The inhibitory action of AMI can be partly compensated by mutations in the translation elongation factor G.
Agid:
5539687