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A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action
Author(s) -
Gigante Alba,
Sijbesma Eline,
SánchezMurcia Pedro A.,
Hu Xiaoyu,
Bier David,
Bäcker Sandra,
Knauer Shirley,
Gago Federico,
Ottmann Christian,
Schmuck Carsten
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201914517
Subject(s) - stabilizer (aeronautics) , chemistry , phosphopeptide , supramolecular chemistry , estrogen receptor , protein–protein interaction , mode of action , stereochemistry , combinatorial chemistry , biophysics , biochemistry , crystallography , peptide , biology , crystal structure , mechanical engineering , engineering , cancer , breast cancer , genetics
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.
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