Shanmugapriya Sothiselvam, Bo Liu, Wei Han, Dorota Klepacki, Gemma C. Atkinson,
Age Brauer, Maido Remm, Tanel Tenson, Klaus Schulten, Nora
Vázquez-Laslop, and Alexander S. Mankin.
Macrolide antibiotics allosterically predispose the ribosome for
translation arrest.
Proceedings of the National Academy of Sciences, USA,
111:9804-9809, 2014.
(PMC: PMC4103360)
SOTH2014
Programmed translation arrest directed by nascent peptides and small cofactors controls
expression of important bacterial and eukaryotic genes. Inducible antibiotic resistance
genes, activated by binding of macrolide molecules to the ribosome, are the
most medically-relevant bacterial genes regulated by such mechanism. Previous studies
suggested that specific interactions between the nascent peptide and the drug molecule
juxtaposed in the ribosomal exit tunnel play a key role in the mechanism of translation
arrest. However, here we show that macrolides can arrest translation of a truncated
regulatory peptide ErmDL when the nascent chain is composed of only three amino acids
and is thus too short to be juxtaposed with the antibiotic. Biochemical probing and all-
atom molecular dynamics simulation of drug-free and erythromycin-bound ribosomes
showed that binding of antibiotic in the tunnel allosterically alters the properties of the
catalytic center, thereby predisposing the ribosome for arrest during translation of
specific amino acid sequences. Our findings provide a principally new view on the role of
small cofactors in the mechanism of programmed translation arrest and reveal an allosteric
link between the exit tunnel and the catalytic center of the ribosome.
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