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Structure of the mammalian antimicrobial peptide Bac7(1-16) bound within the exit tunnel of a bacterial ribosome

Seefeldt, A. Carolin
•
Graf, Michael
•
Pérébaskine, Natacha
altro
Innis, C. Axel
2016
  • journal article

Periodico
NUCLEIC ACIDS RESEARCH
Abstract
Proline-rich antimicrobial peptides (PrAMPs) produced as part of the innate immune response of animals, insects and plants represent a vast, untapped resource for the treatment of multidrug-resistant bacterial infections. PrAMPs such as oncocin or bactenecin-7 (Bac7) interact with the bacterial ribosome to inhibit translation, but their supposed specificity as inhibitors of bacterial rather than mammalian protein synthesis remains unclear, despite being key to developing drugs with low toxicity. Here, we present crystal structures of the Thermus thermophilus 70S ribosome in complex with the first 16 residues of mammalian Bac7, as well as the insect-derived PrAMPs metalnikowin I and pyrrhocoricin. The structures reveal that the mammalian Bac7 interacts with a similar region of the ribosome as insect-derived PrAMPs. Consistently, Bac7 and the oncocin derivative Onc112 compete effectively with antibiotics, such as erythromycin, which target the ribosomal exit tunnel. Moreover, we demonstrate that Bac7 allows initiation complex formation but prevents entry into the elongation phase of translation, and show that it inhibits translation on both mammalian and bacterial ribosomes, explaining why this peptide needs to be stored as an inactive pro-peptide. These findings highlight the need to consider the specificity of PrAMP derivatives for the bacterial ribosome in future drug development efforts.
DOI
10.1093/nar/gkv1545
WOS
WOS:000373723100047
Archivio
http://hdl.handle.net/11368/2894675
info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-84959532218
https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkv1545
Diritti
open access
license:creative commons
license uri:http://creativecommons.org/licenses/by-nc/4.0/
FVG url
https://arts.units.it/bitstream/11368/2894675/4/gkv1545.pdf
Soggetti
  • Amino Acid Sequence

  • Animal

  • Anti-Bacterial Agent

  • Antimicrobial Cationi...

  • Binding Site

  • Binding, Competitive

  • Cattle

  • Crystallography, X-Ra...

  • Erythromycin

  • Escherichia coli

  • Heteroptera

  • Insect Protein

  • Models, Molecular

  • Molecular Sequence Da...

  • Peptides, Cyclic

  • Protein Binding

  • Protein Biosynthesi

  • RNA, Messenger

  • RNA, Transfer

  • Ribosome

  • Species Specificity

  • Thermus thermophilu

  • Genetics

Scopus© citazioni
54
Data di acquisizione
Jun 15, 2022
Vedi dettagli
Web of Science© citazioni
75
Data di acquisizione
Mar 21, 2024
Visualizzazioni
1
Data di acquisizione
Apr 19, 2024
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