Structure and Function of the Bacterial Protein Toxin Phenomycin.
Animals
Bacterial Toxins
/ chemistry
Bacteriocins
/ pharmacokinetics
Cell Line
Endosomes
/ drug effects
Humans
Intercellular Signaling Peptides and Proteins
/ chemistry
MCF-7 Cells
Mice
Mutation
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Protein Synthesis Inhibitors
/ chemistry
Structure-Activity Relationship
NMR structure
cell-penetrating peptide
mini-protein
natural product
protein synthesis inhibitor
protein toxin
ribosome
Journal
Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697
Informations de publication
Date de publication:
05 05 2020
05 05 2020
Historique:
received:
16
12
2019
revised:
19
02
2020
accepted:
09
03
2020
pubmed:
30
3
2020
medline:
11
6
2021
entrez:
30
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32220302
pii: S0969-2126(20)30075-7
doi: 10.1016/j.str.2020.03.003
pii:
doi:
Substances chimiques
Bacterial Toxins
0
Bacteriocins
0
Intercellular Signaling Peptides and Proteins
0
Protein Synthesis Inhibitors
0
phenomycin
12624-22-5
carotovoricin
66812-91-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
528-539.e9Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.