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Mol Cell. 2014 Nov 6;56(3):446-52. doi: 10.1016/j.molcel.2014.09.014. Epub 2014 Oct 8.

Drug sensing by the ribosome induces translational arrest via active site perturbation.

Author information

1
Gene Center and Department for Biochemistry, University of Munich, Feodor-Lynenstr. 25, 81377 Munich, Germany.
2
Center for Pharmaceutical Biotechnology, University of Illinois, Chicago, Chicago, IL 60607, USA.
3
Gene Center and Department for Biochemistry, University of Munich, Feodor-Lynenstr. 25, 81377 Munich, Germany; Center for integrated Protein Science Munich (CiPSM), University of Munich, Feodor-Lynenstr. 25, 81377 Munich, Germany.
4
Gene Center and Department for Biochemistry, University of Munich, Feodor-Lynenstr. 25, 81377 Munich, Germany; Center for integrated Protein Science Munich (CiPSM), University of Munich, Feodor-Lynenstr. 25, 81377 Munich, Germany. Electronic address: wilson@lmb.uni-muenchen.de.

Abstract

During protein synthesis, nascent polypeptide chains within the ribosomal tunnel can act in cis to induce ribosome stalling and regulate expression of downstream genes. The Staphylococcus aureus ErmCL leader peptide induces stalling in the presence of clinically important macrolide antibiotics, such as erythromycin, leading to the induction of the downstream macrolide resistance methyltransferase ErmC. Here, we present a cryo-electron microscopy (EM) structure of the erythromycin-dependent ErmCL-stalled ribosome at 3.9 Å resolution. The structure reveals how the ErmCL nascent chain directly senses the presence of the tunnel-bound drug and thereby induces allosteric conformational rearrangements at the peptidyltransferase center (PTC) of the ribosome. ErmCL-induced perturbations of the PTC prevent stable binding and accommodation of the aminoacyl-tRNA at the A-site, leading to inhibition of peptide bond formation and translation arrest.

PMID:
25306253
PMCID:
PMC4252717
DOI:
10.1016/j.molcel.2014.09.014
[Indexed for MEDLINE]
Free PMC Article

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