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Nat Commun. 2016 Jul 6;7:12026. doi: 10.1038/ncomms12026.

A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest.

Author information

1
Gene Center and Department for Biochemistry, University of Munich, Feodor-Lynenstrasse 25, Munich 81377, Germany.
2
Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen 37079, Germany.
3
Institut Européen de Chimie et Biologie, University of Bordeaux, Pessac 33607, France.
4
INSERM U1212, Bordeaux 33076, France.
5
CNRS UMR7377, Bordeaux 33076, France.
6
Center for integrated Protein Science Munich, University of Munich, Feodor-Lynenstrasse 25, Munich 81377, Germany.

Abstract

Nascent polypeptides can induce ribosome stalling, regulating downstream genes. Stalling of ErmBL peptide translation in the presence of the macrolide antibiotic erythromycin leads to resistance in Streptococcus sanguis. To reveal this stalling mechanism we obtained 3.6-Å-resolution cryo-EM structures of ErmBL-stalled ribosomes with erythromycin. The nascent peptide adopts an unusual conformation with the C-terminal Asp10 side chain in a previously unseen rotated position. Together with molecular dynamics simulations, the structures indicate that peptide-bond formation is inhibited by displacement of the peptidyl-tRNA A76 ribose from its canonical position, and by non-productive interactions of the A-tRNA Lys11 side chain with the A-site crevice. These two effects combine to perturb peptide-bond formation by increasing the distance between the attacking Lys11 amine and the Asp10 carbonyl carbon. The interplay between drug, peptide and ribosome uncovered here also provides insight into the fundamental mechanism of peptide-bond formation.

PMID:
27380950
PMCID:
PMC4935803
DOI:
10.1038/ncomms12026
[Indexed for MEDLINE]
Free PMC Article

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