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Dr. Antonella Paladino Dr. Mark R. Woodford Dr. Sarah J. Backe Dr. Rebecca A. Sager Dr. Priyanka Kancherla Dr. Michael A. Daneshvar Dr. Victor Z. Chen Dimitra Bourboulia Dr. Elham F. Ahanin Dr. Chrisostomos Prodromou Dr. Greta Bergamaschi Dr. Alessandro Strada Dr. Marina Cretich Dr. Alessandro Gori Dr. Marina Veronesi Dr. Tiziano Bandiera Renzo Vanna Dr. Gennady Bratslavsky Stefano A. Serapian Dr. Mehdi Mollapour Prof. Dr. Giorgio Colombo 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(43):9459-9465
Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein–protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation. 相似文献
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