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Charting the sequence-activity landscape of peptide inhibitors of translation termination. | LitMetric

AI Article Synopsis

  • * Research involved creating various mutated versions of Api to identify which amino acid interactions are essential for its function and antibacterial properties.
  • * The study found that certain mutations could preserve Api's effectiveness, while others defined critical interactions with ribosomal components, paving the way for potential improvements in the peptide's pharmacological properties.

Article Abstract

Apidaecin (Api), an unmodified 18-amino-acid-long proline-rich antibacterial peptide produced by bees, has been recently described as a specific inhibitor of translation termination. It invades the nascent peptide exit tunnel of the postrelease ribosome and traps the release factors preventing their recycling. Api binds in the exit tunnel in an extended conformation that matches the placement of a nascent polypeptide and establishes multiple contacts with ribosomal RNA (rRNA) and ribosomal proteins. Which of these interactions are critical for Api's activity is unknown. We addressed this problem by analyzing the activity of all possible single-amino-acid substitutions of the Api variants synthesized in the bacterial cell. By conditionally expressing the engineered gene, we generated Api directly in the bacterial cytosol, thereby bypassing the need for importing the peptide from the medium. The endogenously expressed Api, as well as its N-terminally truncated mutants, retained the antibacterial properties and the mechanism of action of the native peptide. Taking advantage of the Api expression system and next-generation sequencing, we mapped in one experiment all the single-amino-acid substitutions that preserve or alleviate the on-target activity of the Api mutants. Analysis of the inactivating mutations made it possible to define the pharmacophore of Api involved in critical interactions with the ribosome, transfer RNA (tRNA), and release factors. We also identified the Api segment that tolerates a variety of amino acid substitutions; alterations in this segment could be used to improve the pharmacological properties of the antibacterial peptide.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958441PMC
http://dx.doi.org/10.1073/pnas.2026465118DOI Listing

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