Results
Title

A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action.

Authors

Gigante, Alba; Sijbesma, Eline; Sánchez‐Murcia, Pedro A.; Hu, Xiaoyu; Bier, David; Bäcker, Sandra; Knauer, Shirley; Gago, Federico; Ottmann, Christian; Schmuck, Carsten

Abstract

We report on a stabilizer of the interaction between 14‐3‐3ζ and the Estrogen Receptor alpha (ERα). ERα is a driver in the majority of breast cancers and 14‐3‐3 proteins are negative regulators of this nuclear receptor, making the stabilization of this protein‐protein interaction (PPI) an interesting strategy. The stabilizer (1) consists of three symmetric peptidic arms containing an arginine mimetic, previously described as the GCP motif. 1 stabilizes the 14‐3‐3ζ/ERα interaction synergistically with the natural product Fusicoccin‐A and was thus hypothesized to bind to a different site. This is supported by computational analysis of 1 binding to the binary complex of 14‐3‐3 and an ERα‐derived phosphopeptide. Furthermore, 1 shows selectivity towards 14‐3‐3ζ/ERα interaction over other 14‐3‐3 client‐derived phosphomotifs. These data provide a solid support of a new binding mode for a supramolecular 14‐3‐3ζ/ERα PPI stabilizer.

Subjects

PROTEIN-protein interactions; ESTROGEN receptors; NATURAL products; BREAST cancer; BINDING sites; NUCLEAR receptors (Biochemistry); SUPRAMOLECULES

Publication

Angewandte Chemie, 2020, Vol 132, Issue 13, p5322

ISSN

0044-8249

Publication type

Academic Journal

DOI

10.1002/ange.201914517