Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions
Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions(18 views) Paladino A, Woodford MR, Backe SJ, Sager RA, Kancherla P, Daneshvar MA, Chen VZ, Bourboulia D, Ahanin EF, Prodromou C, Bergamaschi G, Strada A, Cretich M, Gori A, Veronesi M, Bandiera T, Vanna R, Bratslavsky G, Serapian SA, Mollapour M, Colombo G
Chemistry (ISSN: 0947-6539linking), 2020 Aug 3; 26
(43
): 9459-9465.
Affiliations: SCITEC-CNR, via Mario Bianco 9, 20131, Milano, Italy.
Department of Urology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
College of Medicine, SUNY Upstate Medical University, Syracuse, NY, 13210, USA.
Genome Damage and Stability Centre, University of Sussex, Brighton, BN1 9RQ, UK.
D3-PharmaChemistry, Istituto Italiano di Tecnologia (IIT), Genova, Italy.
Institute for Photonics and Nanotechnologies, IFN-CNR, c/o Dept. of Physics, Politecnico di Milano, Piazza L. Da Vinci 32, 20133, Milano, Italy.
University of Pavia, Department of Chemistry, Viale Taramelli 10, 27100, Pavia, Italy.
References: Not available.
Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions
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.
Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions
No results.
Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions