Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition

Matthieu Gagnon, Raktim N. Roy, Ivan B. Lomakin, Tanja Florin, Alexander S. Mankin, Thomas A. Steitz

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

With bacterial resistance becoming a serious threat to global public health, antimicrobial peptides (AMPs) have become a promising area of focus in antibiotic research. AMPs are derived from a diverse range of species, from prokaryotes to humans, with a mechanism of action that often involves disruption of the bacterial cell membrane. Proline-rich antimicrobial peptides (PrAMPs) are instead actively transported inside the bacterial cell where they bind and inactivate specific targets. Recently, it was reported that some PrAMPs, such as Bac71-35, oncocins and apidaecins, bind and inactivate the bacterial ribosome. Here we report the crystal structures of Bac71-35, Pyrrhocoricin, Metalnikowin and two oncocin derivatives, bound to the Thermus thermophilus 70S ribosome. Each of the PrAMPs blocks the peptide exit tunnel of the ribosome by simultaneously occupying three well characterized antibiotic-binding sites and interferes with the initiation step of translation, thereby revealing a common mechanism of action used by these PrAMPs to inactivate protein synthesis. Our study expands the repertoire of PrAMPs and provides a framework for designing new-generation therapeutics.

Original languageEnglish (US)
Article number18
Pages (from-to)2439-2450
Number of pages12
JournalNucleic Acids Research
Volume44
Issue number5
DOIs
StatePublished - Jan 24 2016
Externally publishedYes

Fingerprint

Ribosomes
Proline
Peptides
Proteins
Anti-Bacterial Agents
Thermus thermophilus
Public Health
Binding Sites
Cell Membrane
Research

ASJC Scopus subject areas

  • Genetics

Cite this

Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition. / Gagnon, Matthieu; Roy, Raktim N.; Lomakin, Ivan B.; Florin, Tanja; Mankin, Alexander S.; Steitz, Thomas A.

In: Nucleic Acids Research, Vol. 44, No. 5, 18, 24.01.2016, p. 2439-2450.

Research output: Contribution to journalArticle

Gagnon, Matthieu ; Roy, Raktim N. ; Lomakin, Ivan B. ; Florin, Tanja ; Mankin, Alexander S. ; Steitz, Thomas A. / Structures of proline-rich peptides bound to the ribosome reveal a common mechanism of protein synthesis inhibition. In: Nucleic Acids Research. 2016 ; Vol. 44, No. 5. pp. 2439-2450.
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