Structure and Function of the Bacterial Protein Toxin Phenomycin

Bente Kring Hansen, Camilla K Larsen, Jakob T Nielsen, Esben B Svenningsen, Lan B Van, Kristian M Jacobsen, Morten Bjerring, Rasmus K Flygaard, Lasse B Jenner, Lene N Nejsum, Ditlev E Brodersen, Frans A A Mulder, Thomas Tørring, Thomas B. Poulsen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Phenomycin is a bacterial mini-protein of 89 amino acids discovered more than 50 years ago with toxicity in the nanomolar regime toward mammalian cells. The protein inhibits the function of the eukaryotic ribosome in cell-free systems and appears to target translation initiation. Several fundamental questions concerning the cellular activity of phenomycin, however, have remained unanswered. In this paper, we have used morphological profiling to show that direct inhibition of translation underlies the toxicity of phenomycin in cells. We have performed studies of the cellular uptake mechanism of phenomycin, showing that endosomal escape is the toxicity-limiting step, and we have solved a solution phase high-resolution structure of the protein using NMR spectroscopy. Through bioinformatic as well as functional comparisons between phenomycin and two homologs, we have identified a peptide segment, which constitutes one of two loops in the structure that is critical for the toxicity of phenomycin.

Original languageEnglish
JournalStructure
Volume28
Issue5
Pages (from-to)528-539.e9
Number of pages12
ISSN0969-2126
DOIs
Publication statusPublished - 2020

Keywords

  • NMR structure
  • cell-penetrating peptide
  • mini-protein
  • natural product
  • protein synthesis inhibitor
  • protein toxin
  • ribosome

Fingerprint

Dive into the research topics of 'Structure and Function of the Bacterial Protein Toxin Phenomycin'. Together they form a unique fingerprint.

Cite this