A Supramolecular Stabilizer of the 14‐3‐3ζ/ERα Protein‐Protein Interaction with a Synergistic Mode of Action. (11th February 2020)

• Record Type: Journal Article
• Authors: Gigante, Alba; Sijbesma, Eline; Sánchez‐Murcia, Pedro A.; Hu, Xiaoyu; Bier, David; Bäcker, Sandra; Knauer, Shirley; Gago, Federico; Ottmann, Christian; Schmuck, Carsten
• Is Part Of: Angewandte Chemie. Volume 132:Number 13(2020)
• Page Start: 5322
• Page End: 5325
• Publication Date: 2020-02-11
• Subjects: 14-3-3 -- ERα -- Protein-Protein-Wechselwirkung -- Stabilisatoren -- Supramolekulare Systeme; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201914517
• Languages: English
• ISSNs: 0044-8249

Abstract

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. Abstract : Ein Stabilisator der Interaktion zwischen dem Östrogenrezeptor alpha (ERα), einem Einflussfaktor bei den meisten Brustkrebserkrankungen, und 14‐3‐3ζ, einem negativen Regulator von ERα, wird als Anti‐Krebs‐Strategie entwickelt. Der Stabilisator dieser Protein‐Protein‐Interaktion (PPI) besteht aus drei symmetrischen Peptidarmen und stabilisiert die 14‐3‐3ζ/ERα‐Interaktion synergistisch mit dem Naturstoff Fusicoccin‐A.