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

Stefan Arenz, Lars V. Bock, Michael Graf, C. Axel Innis, Roland Beckmann, Helmut Grubmüller, Andrea C. Vaiana () and Daniel N. Wilson ()
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Stefan Arenz: University of Munich
Lars V. Bock: Max Planck Institute for Biophysical Chemistry
Michael Graf: University of Munich
C. Axel Innis: Institut Européen de Chimie et Biologie, University of Bordeaux
Roland Beckmann: University of Munich
Helmut Grubmüller: Max Planck Institute for Biophysical Chemistry
Andrea C. Vaiana: Max Planck Institute for Biophysical Chemistry
Daniel N. Wilson: University of Munich

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12026

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