TCB Publications - Abstract

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.

Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: Journal, Request a Copy