Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9804-9. doi: 10.1073/pnas.1403586111. Epub 2014 Jun 24.

Macrolide antibiotics allosterically predispose the ribosome for translation arrest.

Author information

1
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607;
2
Beckman Institute and Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
3
Institute of Technology, University of Tartu, 50411 Tartu, Estonia;Department of Molecular Biology andLaboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå 90187, Sweden; and.
4
Institute of Molecular and Cell Biology, University of Tartu, 50411 Tartu, Estonia.
5
Institute of Technology, University of Tartu, 50411 Tartu, Estonia;
6
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, IL 60607; shura@uic.edu nvazquez@uic.edu.

Abstract

Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome.

KEYWORDS:

azithromycin; ketolides; solithromycin

PMID:
24961372
PMCID:
PMC4103360
DOI:
10.1073/pnas.1403586111
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center