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Multimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88

Author

Listed:
  • Simon M. Lauer

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin
    Institut für Biologie)

  • Maren Reepmeyer

    (Universität Leipzig
    Universität Leipzig)

  • Ole Berendes

    (Max Planck Institute for Multidisciplinary Sciences)

  • Dorota Klepacki

    (University of Illinois at Chicago)

  • Jakob Gasse

    (Universität Leipzig
    Universität Leipzig)

  • Sara Gabrielli

    (Max Planck Institute for Multidisciplinary Sciences)

  • Helmut Grubmüller

    (Max Planck Institute for Multidisciplinary Sciences)

  • Lars V. Bock

    (Max Planck Institute for Multidisciplinary Sciences)

  • Andor Krizsan

    (Universität Leipzig
    Universität Leipzig)

  • Rainer Nikolay

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin
    Department of Genome Regulation)

  • Christian M. T. Spahn

    (corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin)

  • Ralf Hoffmann

    (Universität Leipzig
    Universität Leipzig)

Abstract

Proline-rich antimicrobial peptides (PrAMPs) inhibit bacterial protein biosynthesis by binding to the polypeptide exit tunnel (PET) near the peptidyl transferase center. Api137, an optimized derivative of honeybee PrAMP apidaecin, inhibits protein expression by trapping release factors (RFs), which interact with stop codons on ribosomes to terminate translation. This study uses cryo-EM, functional assays and molecular dynamic (MD) simulations to show that Api137 additionally occupies a second binding site near the exit of the PET and can repress translation independently of RF-trapping. Api88, a C-terminally amidated (-CONH2) analog of Api137 (-COOH), binds to the same sites, occupies a third binding pocket and interferes with the translation process presumably without RF-trapping. In conclusion, apidaecin-derived PrAMPs inhibit bacterial ribosomes by multimodal mechanisms caused by minor structural changes and thus represent a promising pool for drug development efforts.

Suggested Citation

  • Simon M. Lauer & Maren Reepmeyer & Ole Berendes & Dorota Klepacki & Jakob Gasse & Sara Gabrielli & Helmut Grubmüller & Lars V. Bock & Andor Krizsan & Rainer Nikolay & Christian M. T. Spahn & Ralf Hoff, 2024. "Multimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48027-4
    DOI: 10.1038/s41467-024-48027-4
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    References listed on IDEAS

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    1. Anna B. Loveland & Egor Svidritskiy & Denis Susorov & Soojin Lee & Alexander Park & Sarah Zvornicanin & Gabriel Demo & Fen-Biao Gao & Andrei A. Korostelev, 2022. "Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Lars Ferbitz & Timm Maier & Holger Patzelt & Bernd Bukau & Elke Deuerling & Nenad Ban, 2004. "Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins," Nature, Nature, vol. 431(7008), pages 590-596, September.
    3. Charles R. Harris & K. Jarrod Millman & Stéfan J. Walt & Ralf Gommers & Pauli Virtanen & David Cournapeau & Eric Wieser & Julian Taylor & Sebastian Berg & Nathaniel J. Smith & Robert Kern & Matti Picu, 2020. "Array programming with NumPy," Nature, Nature, vol. 585(7825), pages 357-362, September.
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