title: The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin.
abstract: 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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Raktim N
authors.initials: RN
authors.lastname: Roy
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA.
authors.forename: Ivan B
authors.initials: IB
authors.lastname: Lomakin
authors.affiliation: 1] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. [2] Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA.
authors.forename: Matthieu G
authors.initials: MG
authors.lastname: Gagnon
authors.affiliation: 1] Department of Chemistry, Yale University, New Haven, Connecticut, USA. [2] Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. [3] Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Steitz
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011487:Protein Conformation; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism; D016963:Thermus thermophilus / Q000737:chemistry / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D011500:Protein Synthesis Inhibitors; C551620:oncocin