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Toxins 2018, 10(9), 371; https://doi.org/10.3390/toxins10090371

Peptide Mimics of the Ribosomal P Stalk Inhibit the Activity of Ricin A Chain by Preventing Ribosome Binding

Department of Plant Biology, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8520, USA
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Received: 10 August 2018 / Revised: 7 September 2018 / Accepted: 10 September 2018 / Published: 13 September 2018
(This article belongs to the Special Issue Ricin Toxins)
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Abstract

Ricin A chain (RTA) depurinates the sarcin/ricin loop (SRL) by interacting with the C-termini of the ribosomal P stalk. The ribosome interaction site and the active site are located on opposite faces of RTA. The interaction with P proteins allows RTA to depurinate the SRL on the ribosome at physiological pH with an extremely high activity by orienting the active site towards the SRL. Therefore, if an inhibitor disrupts RTA–ribosome interaction by binding to the ribosome binding site of RTA, it should inhibit the depurination activity. To test this model, we synthesized peptides mimicking the last 3 to 11 amino acids of P proteins and examined their interaction with wild-type RTA and ribosome binding mutants by Biacore. We measured the inhibitory activity of these peptides on RTA-mediated depurination of yeast and rat liver ribosomes. We found that the peptides interacted with the ribosome binding site of RTA and inhibited depurination activity by disrupting RTA–ribosome interactions. The shortest peptide that could interact with RTA and inhibit its activity was four amino acids in length. RTA activity was inhibited by disrupting its interaction with the P stalk without targeting the active site, establishing the ribosome binding site as a new target for inhibitor discovery. View Full-Text
Keywords: ricin A chain; ribosomal P stalk; P protein interaction; SRL depurination; peptide inhibition ricin A chain; ribosomal P stalk; P protein interaction; SRL depurination; peptide inhibition
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Li, X.-P.; Kahn, J.N.; Tumer, N.E. Peptide Mimics of the Ribosomal P Stalk Inhibit the Activity of Ricin A Chain by Preventing Ribosome Binding. Toxins 2018, 10, 371.

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