Blasticidin S inhibits translation by trapping deformed tRNA on the ribosome

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Abstract

The antibiotic blasticidin S (BlaS) is a potent inhibitor of protein synthesis in bacteria and eukaryotes. We have determined a 3.4-Å crystal structure of BlaS bound to a 70StRNA ribosome complex and performed biochemical and single-molecule FRET experiments to determine the mechanism of action of the antibiotic. We find that BlaS enhances tRNA binding to the P site of the large ribosomal subunit and slows down spontaneous intersubunit rotation in pretranslocation ribosomes. However, the antibiotic has negligible effect on elongation factor G catalyzed translocation of tRNA and mRNA. The crystal structure of the antibiotic-ribosome complex reveals that BlaS impedes protein synthesis through a unique mechanism by bending the 3' terminus of the P-site tRNA toward the A site of the large ribosomal subunit. Biochemical experiments demonstrate that stabilization of the deformed conformation of the P-site tRNA by BlaS strongly inhibits peptidyl-tRNA hydrolysis by release factors and, to a lesser extent, peptide bond formation.

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Svidritskiy, E., Ling, C., Ermolenko, D. N., & Korostelev, A. A. (2013). Blasticidin S inhibits translation by trapping deformed tRNA on the ribosome. Proceedings of the National Academy of Sciences of the United States of America, 110(30), 12283–12288. https://doi.org/10.1073/pnas.1304922110

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