The proline-rich antimicrobial peptide Onc112 inhibits translation by blocking and destabilizing the initiation complex

• Published in: Nature structural & molecular biology Vol. 22; no. 6; pp. 470 - 475
• Main Authors: Seefeldt, A Carolin, Nguyen, Fabian, Antunes, Stéphanie, Pérébaskine, Natacha, Graf, Michael, Arenz, Stefan, Inampudi, K Kishore, Douat, Céline, Guichard, Gilles, Wilson, Daniel N, Innis, C Axel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-06-2015; Nature Publishing Group
• Subjects: 631/154; 631/326/421; 631/535; 692/699; Antibiotics; Antimicrobial agents; Antimicrobial Cationic Peptides - metabolism; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial peptides; Bacteria; Biochemistry; Biological Microscopy; Crystallography; Crystallography, X-Ray; Life Sciences; Membrane Biology; Mode of action; Models, Molecular; Peptide Chain Initiation, Translational - drug effects; Peptides; Physiological aspects; Protein Conformation; Protein Structure; Protein Synthesis Inhibitors - metabolism; Protein Synthesis Inhibitors - pharmacology; Ribonucleic acid; Ribosomes - chemistry; Ribosomes - metabolism; RNA; Structure; Thermus thermophilus; Thermus thermophilus - chemistry; Thermus thermophilus - drug effects; Transfer RNA; France
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.3034

Structural and biochemical studies reveal how the antimicrobial peptide Onc112 binds to bacterial ribosomes and show that Onc112 blocks and destabilizes the translation-initiation complex.
The increasing prevalence of multidrug-resistant pathogenic bacteria is making current antibiotics obsolete. Proline-rich antimicrobial peptides (PrAMPs) display potent activity against Gram-negative bacteria and thus represent an avenue for antibiotic development. PrAMPs from the oncocin family interact with the ribosome to inhibit translation, but their mode of action has remained unclear. Here we have determined a structure of the Onc112 peptide in complex with the
Thermus thermophilus
70S ribosome at a resolution of 3.1 Å by X-ray crystallography. The Onc112 peptide binds within the ribosomal exit tunnel and extends toward the peptidyl transferase center, where it overlaps with the binding site for an aminoacyl-tRNA. We show biochemically that the binding of Onc112 blocks and destabilizes the initiation complex, thus preventing entry into the elongation phase. Our findings provide a basis for the future development of this class of potent antimicrobial agents.