Structure and Function of the Bacterial Protein Toxin Phenomycin

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Structure and Function of the Bacterial Protein Toxin Phenomycin. / Hansen, Bente Kring; Larsen, Camilla K; Nielsen, Jakob T; Svenningsen, Esben B; Van, Lan B; Jacobsen, Kristian M; Bjerring, Morten; Flygaard, Rasmus K; Jenner, Lasse B; Nejsum, Lene N; Brodersen, Ditlev E; Mulder, Frans A A; Tørring, Thomas; Poulsen, Thomas B.

I: Structure, Bind 28, Nr. 5, 2020, s. 528-539.e9.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{b55a6a6830c841f5a29710d15998bede,
title = "Structure and Function of the Bacterial Protein Toxin Phenomycin",
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.",
keywords = "NMR structure, cell-penetrating peptide, mini-protein, natural product, protein synthesis inhibitor, protein toxin, ribosome",
author = "Hansen, {Bente Kring} and Larsen, {Camilla K} and Nielsen, {Jakob T} and Svenningsen, {Esben B} and Van, {Lan B} and Jacobsen, {Kristian M} and Morten Bjerring and Flygaard, {Rasmus K} and Jenner, {Lasse B} and Nejsum, {Lene N} and Brodersen, {Ditlev E} and Mulder, {Frans A A} and Thomas T{\o}rring and Poulsen, {Thomas B.}",
note = "Copyright {\textcopyright} 2020 Elsevier Ltd. All rights reserved.",
year = "2020",
doi = "10.1016/j.str.2020.03.003",
language = "English",
volume = "28",
pages = "528--539.e9",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "5",

}

RIS

TY - JOUR

T1 - Structure and Function of the Bacterial Protein Toxin Phenomycin

AU - Hansen, Bente Kring

AU - Larsen, Camilla K

AU - Nielsen, Jakob T

AU - Svenningsen, Esben B

AU - Van, Lan B

AU - Jacobsen, Kristian M

AU - Bjerring, Morten

AU - Flygaard, Rasmus K

AU - Jenner, Lasse B

AU - Nejsum, Lene N

AU - Brodersen, Ditlev E

AU - Mulder, Frans A A

AU - Tørring, Thomas

AU - Poulsen, Thomas B.

N1 - Copyright © 2020 Elsevier Ltd. All rights reserved.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - NMR structure

KW - cell-penetrating peptide

KW - mini-protein

KW - natural product

KW - protein synthesis inhibitor

KW - protein toxin

KW - ribosome

UR - http://www.scopus.com/inward/record.url?scp=85083019610&partnerID=8YFLogxK

U2 - 10.1016/j.str.2020.03.003

DO - 10.1016/j.str.2020.03.003

M3 - Journal article

C2 - 32220302

VL - 28

SP - 528-539.e9

JO - Structure

JF - Structure

SN - 0969-2126

IS - 5

ER -