The mechanism of inhibition
Researchers using the NE-CAT 24-ID-E beamline at the APS are exploring how to develop new effective therapeutics to fight antibiotic-resistant bacteria. The results have been reported in Nature Structural and Molecular Biology.
Throughout the course of evolution, the innate immune system in plants and animals has developed efficient ways to counter infections. One of the lines of defense is through the synthesis of Antimicrobial Peptides (AMPs) that kill bacterial and fungal pathogens. These AMPs are an effective weapon against the ability of microorganisms to develop resistance.
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.
Raktim N Roy, Ivan B Lomakin, Matthieu G Gagnon and Thomas A Steitz, “The Mechanism of Inhibition of Protein Synthesis by the Proline-rich Peptide Oncocin,” Nature Structural and Molecular Biology, Article. DOI: 10.1038/nsmb.3031, Published Online May 18, 2015.