7OBT

Crystal structure of 14-3-3 sigma in complex with RIPK2 phosphopeptide and stabilizer Fusicoccin-A

Summary for 7OBT

• Entry DOI: 10.2210/pdb7obt/pdb
• Descriptor: 14-3-3 protein sigma, Receptor-interacting serine/threonine-protein kinase 2, FUSICOCCIN, ... (6 entities in total)
• Functional Keywords: 14-3-3 protein protein-peptide-stabilizer complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30316.85

Authors

Centorrino, F.,Andlovic, B.,Ottmann, C. (deposition date: 2021-04-23, release date: 2022-05-04, Last modification date: 2024-02-07)

Primary citation

Andlovic, B.,Heilmann, G.,Ninck, S.,Andrei, S.A.,Centorrino, F.,Higuchi, Y.,Kato, N.,Brunsveld, L.,Arkin, M.,Menninger, S.,Choidas, A.,Wolf, A.,Klebl, B.,Kaschani, F.,Kaiser, M.,Eickhoff, J.,Ottmann, C.
IFN alpha primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization.
Cell Chem Biol, 2023

PubMed Abstract: The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells. Among the identified 14-3-3 target proteins are THEMIS2, receptor interacting protein kinase 2 (RIPK2), EIF2AK2, and several members of the LDB1 complex. Biophysical and structural biology studies confirm these 14-3-3 PPIs as physical targets of FC stabilization, and transcriptome as well as pathway analyses suggest possible explanations for the observed synergistic effect of IFNα/FC treatment on cancer cells. This study elucidates the polypharmacological effects of FCs in cancer cells and identifies potential targets from the vast interactome of 14-3-3s for therapeutic intervention in oncology.

PubMed: 37130519
DOI: 10.1016/j.chembiol.2023.04.005

Experimental method

X-RAY DIFFRACTION (2.3 Å)