title: The proline-rich antimicrobial peptide Onc112 inhibits translation by blocking and destabilizing the initiation complex.
abstract: 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.
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] INSERM U869, Bordeaux, France.
authors.forename: A Carolin
authors.initials: AC
authors.lastname: Seefeldt
authors.affiliation: Gene Center, Department of Biochemistry, University of Munich, Munich, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Nguyen
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] Université de Bordeaux, CNRS, Institut Polytechnique de Bordeaux, UMR 5248, Institut de Chimie et Biologie des Membranes et des Nano-objets (CBMN), Pessac, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Antunes
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] INSERM U869, Bordeaux, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Pérébaskine
authors.affiliation: Gene Center, Department of Biochemistry, University of Munich, Munich, Germany.
authors.forename: Michael
authors.identifier: 0000000248793834
authors.initials: M
authors.lastname: Graf
authors.affiliation: Gene Center, Department of Biochemistry, University of Munich, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Arenz
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] INSERM U869, Bordeaux, France.
authors.forename: K Kishore
authors.initials: KK
authors.lastname: Inampudi
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] Université de Bordeaux, CNRS, Institut Polytechnique de Bordeaux, UMR 5248, Institut de Chimie et Biologie des Membranes et des Nano-objets (CBMN), Pessac, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Douat
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] Université de Bordeaux, CNRS, Institut Polytechnique de Bordeaux, UMR 5248, Institut de Chimie et Biologie des Membranes et des Nano-objets (CBMN), Pessac, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Guichard
authors.affiliation: 1] Gene Center, Department of Biochemistry, University of Munich, Munich, Germany. [2] Center for Integrated Protein Science Munich (CiPSM), University of Munich, Munich, Germany.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Wilson
authors.affiliation: 1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] INSERM U869, Bordeaux, France.
authors.forename: C Axel
authors.initials: CA
authors.lastname: Innis
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects*; D011487:Protein Conformation; D011500:Protein Synthesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D012270:Ribosomes / Q000737:chemistry* / Q000378:metabolism; D016963:Thermus thermophilus / Q000737:chemistry / Q000187:drug effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D011500:Protein Synthesis Inhibitors