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

Raktim N. Roy, Ivan B. Lomakin, Matthieu Gagnon, Thomas A. Steitz

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)466-469
Number of pages4
JournalNature Structural and Molecular Biology
Volume22
Issue number6
DOIs
StatePublished - Jun 3 2015
Externally publishedYes

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Ribosomes
Proline
Peptides
Proteins
Peptidyl Transferases
Thermus thermophilus
Bacteria
Adenosine Monophosphate
Bacterial Infections
Anti-Bacterial Agents
Membranes
oncocin
Therapeutics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin. / Roy, Raktim N.; Lomakin, Ivan B.; Gagnon, Matthieu; Steitz, Thomas A.

In: Nature Structural and Molecular Biology, Vol. 22, No. 6, 03.06.2015, p. 466-469.

Research output: Contribution to journalArticle

Roy, Raktim N. ; Lomakin, Ivan B. ; Gagnon, Matthieu ; Steitz, Thomas A. / The mechanism of inhibition of protein synthesis by the proline-rich peptide oncocin. In: Nature Structural and Molecular Biology. 2015 ; Vol. 22, No. 6. pp. 466-469.
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