Specific inhibition of the Survivin–CRM1 interaction by peptide-modified molecular tweezers

Annika Meiners, Sandra Bäcker, Inesa Hadrović, Christian Heid, Christine Beuck, Yasser B. Ruiz-Blanco, Joel Mieres-Perez, Marius Pörschke, Jean-Noël Grad, Cecilia Vallet, Daniel Hoffmann, Peter Bayer, Elsa Sánchez-García (), Thomas Schrader () and Shirley K. Knauer ()
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Annika Meiners: University of Duisburg-Essen
Sandra Bäcker: University of Duisburg-Essen
Inesa Hadrović: University of Duisburg-Essen
Christian Heid: University of Duisburg-Essen
Christine Beuck: University of Duisburg-Essen
Yasser B. Ruiz-Blanco: University of Duisburg-Essen
Joel Mieres-Perez: University of Duisburg-Essen
Marius Pörschke: University of Duisburg-Essen
Jean-Noël Grad: University of Duisburg-Essen
Cecilia Vallet: University of Duisburg-Essen
Daniel Hoffmann: University of Duisburg-Essen
Peter Bayer: University of Duisburg-Essen
Elsa Sánchez-García: University of Duisburg-Essen
Thomas Schrader: University of Duisburg-Essen
Shirley K. Knauer: University of Duisburg-Essen

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21753-9

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DOI: 10.1038/s41467-021-21753-9

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