000K utf8 1100 2021$c2021-03-08 1500 eng 2050 urn:nbn:de:hbz:465-20240826-150432-4 2051 10.1038/s41467-021-21753-9 3000 Meiners, Annika 3010 Bäcker, Sandra 3010 Bayer, Peter 3010 Beuck, Christine 3010 Grad, Jean-Noël 3010 Hadrović, Inesa 3010 Heid, Christian 3010 Hoffmann, Daniel 3010 Knauer, Shirley K. 3010 Mieres-Perez, Joel 3010 Pörschke, Marius 3010 Ruiz-Blanco, Yasser B. 3010 Sánchez-García, Elsa 3010 Schrader, Thomas 3010 Vallet, Cecilia 4000 Specific inhibition of the Survivin–CRM1 interaction by peptide-modified molecular tweezers [Meiners, Annika] 4209 Survivin’s dual function as apoptosis inhibitor and regulator of cell proliferation is mediated via its interaction with the export receptor CRM1. This protein–protein interaction represents an attractive target in cancer research and therapy. Here, we report a sophisticated strategy addressing Survivin’s nuclear export signal (NES), the binding site of CRM1, with advanced supramolecular tweezers for lysine and arginine. These were covalently connected to small peptides resembling the natural, self-complementary dimer interface which largely overlaps with the NES. Several biochemical methods demonstrated sequence-selective NES recognition and interference with the critical receptor interaction. These data were strongly supported by molecular dynamics simulations and multiscale computational studies. Rational design of lysine tweezers equipped with a peptidic recognition element thus allowed to address a previously unapproachable protein surface area. As an experimental proof-of-principle for specific transport signal interference, this concept should be transferable to any protein epitope with a flanking well-accessible lysine. 4950 https://doi.org/10.1038/s41467-021-21753-9$xR$3Volltext$534 4950 https://nbn-resolving.org/urn:nbn:de:hbz:465-20240826-150432-4$xR$3Volltext$534 4961 https://duepublico2.uni-due.de/receive/duepublico_mods_00078019 5051 540 5051 570 5550 Cancer 5550 Chemical biology 5550 Chemistry 5550 Molecular biology