7AZY

Context-specific inhibition of eukaryotic translation by macrolide antibiotics

This is a non-PDB format compatible entry.

Summary for 7AZY

• Entry DOI: 10.2210/pdb7azy/pdb
• EMDB information: 11951
• Descriptor: 60S ribosomal protein L8-A, 60S ribosomal protein L13-A, 60S ribosomal protein L26-A, ... (44 entities in total)
• Functional Keywords: context-specific inhibition, macrolide antibiotic, ribosome, telithromycin
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 42
• Total formula weight: 1916774.59

Authors

Koller, T.O.,Wilson, D.N. (deposition date: 2020-11-17, release date: 2021-05-19, Last modification date: 2024-07-10)

Primary citation

Svetlov, M.S.,Koller, T.O.,Meydan, S.,Shankar, V.,Klepacki, D.,Polacek, N.,Guydosh, N.R.,Vazquez-Laslop, N.,Wilson, D.N.,Mankin, A.S.
Context-specific action of macrolide antibiotics on the eukaryotic ribosome.
Nat Commun, 12:2803-2803, 2021

PubMed Abstract: 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.

PubMed: 33990576
DOI: 10.1038/s41467-021-23068-1

Experimental method

ELECTRON MICROSCOPY (2.877 Å)