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Functional Interactions Between Ribosome and Nascent Peptide Mediated By Small Molecules

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posted on 01.07.2016 by Shanmugapriya Sothiselvam
Translation arrest directed by nascent peptides and small cofactors controls expression of important bacterial and eukaryotic genes, including antibiotic resistance genes, activated by binding of macrolide drugs to the ribosome. Previous studies suggested that specific interactions between the nascent peptide and the antibiotic in the ribosomal exit tunnel play a central role in triggering ribosome stalling. However, here we show that macrolides arrest translation of the truncated ErmDL regulatory peptide when the nascent chain is only three amino acids and therefore is too short to be juxtaposed with the antibiotic. Biochemical probing and molecular dynamics simulations of erythromycin-bound ribosomes showed that the antibiotic in the tunnel allosterically alters the properties of the catalytic center, thereby predisposing the ribosome for halting translation of specific sequences. We show that ‘R/K-X-R/K’ is one such problematic sequence for drug bound ribosomes to synthesize. Peptide bond formation is inhibited between positively charged donor and acceptor substrates in the drug bound ribosome. Further, we elucidate how the nature of the amino acids preceding the arrest sequence in the peptide also impacts translation arrest. Our findings offer a new view on the role of small cofactors in the mechanism of translation arrest and reveal an allosteric link between the tunnel and the catalytic center of the ribosome and how a predisposed ribosome inhibits catalysis between specific donor and acceptor substrates by discriminating them based on their charge and size.

History

Advisor

Mankin, Alexander

Department

Medicinal Chemistry and Pharmacognosy

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Federle, Michael Kay, Brian Simonovic, Miljan Vazquez-Laslop, Nora Polikanov, Yury

Submitted date

2016-05

Language

en

Issue date

01/07/2016

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