REL 2023-09-20 2023-11-06 2023-11-06 0000-0003-0145-4891 Timm Oliver Koller University of Hamburg Martin-Luther-King-Platz 6A Hamburg Hamburg Germany 20146 0000-0003-3816-3828 Daniel N Wilson University of Hamburg Martin-Luther-King-Platz 6A Hamburg Hamburg Germany 20146 Koller TO Wilson DN 3.4 10.6019/EMPIAR-11757 EMDB molecule EMD-11951 Svetlov MS Koller TO Meydan S Shankar V Klepacki D Polacek N Guydosh NR Vázquez-Laslop N Wilson DN Mankin AS Nature communications Nat Commun 1 12 2021 English 10.1038/s41467-021-23068-1 33990576

Macrolide antibiotics bind in the nascent peptide exit tunnel of the bacterial ribosome and prevent polymerization of specific amino acid sequences, selectively inhibiting translation of a subset of proteins. Because preventing translation of individual proteins could be beneficial for the treatment of human diseases, we asked whether macrolides, if bound to the eukaryotic ribosome, would retain their context- and protein-specific action. By introducing a single mutation in rRNA, we rendered yeast Saccharomyces cerevisiae cells sensitive to macrolides. Cryo-EM structural analysis showed that the macrolide telithromycin binds in the tunnel of the engineered eukaryotic ribosome. Genome-wide analysis of cellular translation and biochemical studies demonstrated that the drug inhibits eukaryotic translation by preferentially stalling ribosomes at distinct sequence motifs. Context-specific action markedly depends on the macrolide structure. Eliminating macrolide-arrest motifs from a protein renders its translation macrolide-tolerant. Our data illuminate the prospects of adapting macrolides for protein-selective translation inhibition in eukaryotic cells.

Unaligned multi-frame movies of the Saccharomyces cerevisiae 80S (mutant G2400A) with Telithromycin /data/Movies micrographs - multiframe MRCS MRCS 4371 30 UNSIGNED 16 BIT INTEGER 3838 0.82 3710 0.82