Context-specific action of macrolide antibiotics on the eukaryotic ribosome

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F21%3A00124436" target="_blank" >RIV/00216224:14740/21:00124436 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.nature.com/articles/s41467-021-23068-1" target="_blank" >https://www.nature.com/articles/s41467-021-23068-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-021-23068-1" target="_blank" >10.1038/s41467-021-23068-1</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Context-specific action of macrolide antibiotics on the eukaryotic ribosome

Popis výsledku v původním jazyce

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. Macrolide antibiotics inhibit bacterial translation in a context-specific manner, arresting ribosomes at defined sites within mRNAs and selectively inhibiting synthesis of only a subset of cellular proteins. Here the authors provide a structural basis for the context-specific activity of macrolides on the eukaryotic ribosome.

Název v anglickém jazyce

Context-specific action of macrolide antibiotics on the eukaryotic ribosome

Popis výsledku anglicky

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. Macrolide antibiotics inhibit bacterial translation in a context-specific manner, arresting ribosomes at defined sites within mRNAs and selectively inhibiting synthesis of only a subset of cellular proteins. Here the authors provide a structural basis for the context-specific activity of macrolides on the eukaryotic ribosome.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

—

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

—

Svazek periodika

12

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

14

Strana od-do

2803

Kód UT WoS článku

000658675200003

EID výsledku v databázi Scopus

2-s2.0-85105908577