Specific inhibition of the Survivin-CRM1 interaction by peptide-modified molecular tweezers.
Binding Sites
Cell Proliferation
Humans
Inhibitor of Apoptosis Proteins
/ metabolism
Karyopherins
/ chemistry
Models, Molecular
Nuclear Export Signals
Protein Binding
Protein Conformation
Protein Interaction Domains and Motifs
/ drug effects
Receptors, Cytoplasmic and Nuclear
/ chemistry
Survivin
/ chemistry
Exportin 1 Protein
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 03 2021
08 03 2021
Historique:
received:
03
02
2020
accepted:
02
02
2021
entrez:
9
3
2021
pubmed:
10
3
2021
medline:
23
3
2021
Statut:
epublish
Résumé
Survivin's dual function as apoptosis inhibitor and regulator of cell proliferation is mediated via its interaction with the export receptor CRM1. This protein-protein interaction represents an attractive target in cancer research and therapy. Here, we report a sophisticated strategy addressing Survivin's nuclear export signal (NES), the binding site of CRM1, with advanced supramolecular tweezers for lysine and arginine. These were covalently connected to small peptides resembling the natural, self-complementary dimer interface which largely overlaps with the NES. Several biochemical methods demonstrated sequence-selective NES recognition and interference with the critical receptor interaction. These data were strongly supported by molecular dynamics simulations and multiscale computational studies. Rational design of lysine tweezers equipped with a peptidic recognition element thus allowed to address a previously unapproachable protein surface area. As an experimental proof-of-principle for specific transport signal interference, this concept should be transferable to any protein epitope with a flanking well-accessible lysine.
Identifiants
pubmed: 33686072
doi: 10.1038/s41467-021-21753-9
pii: 10.1038/s41467-021-21753-9
pmc: PMC7940618
doi:
Substances chimiques
BIRC5 protein, human
0
Inhibitor of Apoptosis Proteins
0
Karyopherins
0
Nuclear Export Signals
0
Receptors, Cytoplasmic and Nuclear
0
Survivin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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