A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action |
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Authors: | Alba Gigante,Eline Sijbesma,Pedro A. S nchez‐Murcia,Xiaoyu Hu,David Bier,Sandra B cker,Shirley Knauer,Federico Gago,Christian Ottmann,Carsten Schmuck |
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Affiliation: | Alba Gigante,Eline Sijbesma,Pedro A. Sánchez‐Murcia,Xiaoyu Hu,David Bier,Sandra Bäcker,Shirley Knauer,Federico Gago,Christian Ottmann,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. |
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Keywords: | 14-3-3 ERα protein-protein interaction stabilizers supramolecular systems |
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