A supramolecular stabilizer of the 14-3-3ζ/ERα protein-protein interaction with a synergistic mode of action

Alba Gigante, Eline Sijbesma, Pedro A. Sánchez-Murcia, Xiaoyu Hu, David Bier, Sandra Bäcker, Shirley Knauer, Federico Gago, Christian Ottmann (Corresponding author), Carsten Schmuck

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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.

Original languageEnglish
Pages (from-to)5284-5287
Number of pages4
JournalAngewandte Chemie - International Edition
Volume59
Issue number13
DOIs
Publication statusPublished - 11 Feb 2020

Keywords

  • 14-3-3
  • ERα
  • protein-protein interaction
  • stabilizers
  • supramolecular systems

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    Gigante, A., Sijbesma, E., Sánchez-Murcia, P. A., Hu, X., Bier, D., Bäcker, S., Knauer, S., Gago, F., Ottmann, C., & Schmuck, C. (2020). A supramolecular stabilizer of the 14-3-3ζ/ERα protein-protein interaction with a synergistic mode of action. Angewandte Chemie - International Edition, 59(13), 5284-5287. https://doi.org/10.1002/anie.201914517