Context-specific action of macrolide antibiotics on the
eukaryotic ribosome

J 2021

Context-specific action of macrolide antibiotics on the eukaryotic ribosome

SVETLOV, M.S., T.O. KOLLER, S. MEYDAN, V. SHANKAR, D. KLEPACKI et. al.

Basic information

Original name

Context-specific action of macrolide antibiotics on the eukaryotic ribosome

Authors

SVETLOV, M.S., T.O. KOLLER, S. MEYDAN, V. SHANKAR, D. KLEPACKI, N. POLACEK, N.R. GUYDOSH, N. VAZQUEZ-LASLOP, D.N. WILSON and A.S. MANKIN

Edition

Nature Communications, London, Nature Publishing Group, 2021, 2041-1723

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 17.694

RIV identification code

RIV/00216224:14740/21:00124436

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1038/s41467-021-23068-1

UT WoS

000658675200003

Keywords in English

PEPTIDYL TRANSFERASE CENTERNASCENT PEPTIDETRANSLATION ELONGATIONPOLYPROLINE STRETCHESSTRUCTURAL BASISBREAST-CANCERRNAERYTHROMYCINRESISTANCESEQUENCE

Abstract

V originále

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.

Links

90043, large research infrastructures

Name: CIISB

Citovat

SVETLOV, M.S., T.O. KOLLER, S. MEYDAN, V. SHANKAR, D. KLEPACKI, N. POLACEK, N.R. GUYDOSH, N. VAZQUEZ-LASLOP, D.N. WILSON and A.S. MANKIN. Context-specific action of macrolide antibiotics on the eukaryotic ribosome. Nature Communications. London: Nature Publishing Group, 2021, vol. 12, No 1, p. 2803-2816. ISSN 2041-1723. Available from: https://dx.doi.org/10.1038/s41467-021-23068-1.

@article{1842603,
   author = {Svetlov, M.S. and Koller, T.O. and Meydan, S. and Shankar, V. and Klepacki, D. and Polacek, N. and Guydosh, N.R. and VazquezandLaslop, N. and Wilson, D.N. and Mankin, A.S.},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41467-021-23068-1},
   keywords = {PEPTIDYL TRANSFERASE CENTERNASCENT PEPTIDETRANSLATION ELONGATIONPOLYPROLINE STRETCHESSTRUCTURAL BASISBREAST-CANCERRNAERYTHROMYCINRESISTANCESEQUENCE},
   language = {eng},
   issn = {2041-1723},
   journal = {Nature Communications},
   title = {Context-specific action of macrolide antibiotics on the eukaryotic ribosome},
   url = {https://www.nature.com/articles/s41467-021-23068-1},
   volume = {12},
   year = {2021}
}

TY  - JOUR
ID  - 1842603
AU  - 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.
PY  - 2021
TI  - Context-specific action of macrolide antibiotics on the eukaryotic ribosome
JF  - Nature Communications
VL  - 12
IS  - 1
SP  - 2803
EP  - 2803
PB  - Nature Publishing Group
SN  - 20411723
KW  - PEPTIDYL TRANSFERASE CENTERNASCENT PEPTIDETRANSLATION ELONGATIONPOLYPROLINE STRETCHESSTRUCTURAL BASISBREAST-CANCERRNAERYTHROMYCINRESISTANCESEQUENCE
UR  - https://www.nature.com/articles/s41467-021-23068-1
N2  - 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.
ER  -

SVETLOV, M.S., T.O. KOLLER, S. MEYDAN, V. SHANKAR, D. KLEPACKI, N. POLACEK, N.R. GUYDOSH, N. VAZQUEZ-LASLOP, D.N. WILSON and A.S. MANKIN. Context-specific action of macrolide antibiotics on the eukaryotic ribosome. \textit{Nature Communications}. London: Nature Publishing Group, 2021, vol.~12, No~1, p.~2803-2816. ISSN~2041-1723. Available from: https://dx.doi.org/10.1038/s41467-021-23068-1.

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