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Nat Struct Mol Biol. 2015 Jun;22(6):470-5. doi: 10.1038/nsmb.3034. Epub 2015 May 18.

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

Author information

1
1] Institut Européen de Chimie et Biologie, Université de Bordeaux, Pessac, France. [2] INSERM U869, Bordeaux, France.
2
Gene Center, Department of Biochemistry, University of Munich, Munich, Germany.
3
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.
4
1] Gene Center, Department of Biochemistry, University of Munich, Munich, Germany. [2] Center for Integrated Protein Science Munich (CiPSM), University of Munich, Munich, Germany.

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.

PMID:
25984971
DOI:
10.1038/nsmb.3034
[Indexed for MEDLINE]

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