The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin

• Published in: Nature structural & molecular biology Vol. 22; no. 6; pp. 466 - 469
• Main Authors: Roy, Raktim N, Lomakin, Ivan B, Gagnon, Matthieu G, Steitz, Thomas A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2015; Nature Publishing Group
• Subjects: 631/535/1266; Antibiotic resistance; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - metabolism; Antimicrobial Cationic Peptides - pharmacology; Bacteria; Bacterial diseases; Biochemistry; Biological Microscopy; Crystal structure; Crystallography, X-Ray; Drug resistance; Global health; Life Sciences; Membrane Biology; Models, Molecular; Peptides; Physiological aspects; Protein biosynthesis; Protein Conformation; Protein Structure; Protein synthesis; Protein Synthesis Inhibitors - chemistry; Protein Synthesis Inhibitors - metabolism; Protein Synthesis Inhibitors - pharmacology; Proteins; Ribosomes - chemistry; Ribosomes - metabolism; Structure; Thermus thermophilus - chemistry; Thermus thermophilus - metabolism; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.3031

The crystal structure of the thermophilic 70S ribosome bound to the antimicrobial peptide Onc112 reveals that the peptide interacts with three adjacent functional sites in the ribosome. Antibiotic-resistant bacteria are a global health issue necessitating the development of new effective therapeutics. Proline-rich antimicrobial peptides (PrAMPs), which include oncocins, are an extensively studied class of AMPs that counteract bacterial infection at submicromolar concentrations. Oncocins enter and kill bacteria by inhibiting certain targets rather than by acting through membrane lysis. Although they have recently been reported to bind DnaK and the bacterial ribosome, their mode of inhibition has remained elusive. Here we report the crystal structure of the oncocin derivative Onc112 bound to the Thermus thermophilus 70S ribosome. Strikingly, this 19-residue proline-rich peptide manifests the features of several known classes of ribosome inhibitors by simultaneously blocking the peptidyl transferase center and the peptide-exit tunnel of the ribosome. This high-resolution structure thus reveals the mechanism by which oncocins inhibit protein synthesis, providing an opportunity for structure-based design of new-generation therapeutics.