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Journal Article

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

MPS-Authors
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Berendes,  Ole
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Gabrielli,  Sara
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Grubmüller,  Helmut       
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Bock,  Lars V.
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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s41467-024-48027-4.pdf
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Citation

Lauer, S., Reepmeyer, M., Berendes, O., Klepacki, D., Gasse, J., Gabrielli, S., et al. (2024). Multimodal binding and inhibition of bacterial ribosomes by the antimicrobial peptides Api137 and Api88. Nature Communications, 15: 3945. doi:10.1038/s41467-024-48027-4.


Cite as: https://hdl.handle.net/21.11116/0000-000F-553D-E
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.