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‐Pérez, Marius Pörschke, Jean‐Noël Grad, Cecilia Vallet, Daniel Hoffmann, Peter Bayer, Elsa Sánchez‐García, Thomas Schräder, Shirley K. Knauer
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.