Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions (18 views)
Chemistry (ISSN: 0947-6539linking), 2020 Aug 3; 26 (43 ): 9459-9465.
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Paper type: Journal Article
Impact factor: 0, 5-year impact factor: 0
Url: Not available.
Keywords: Carcinogens Chemistry Metabolism , Cell Cycle Proteins Chemistry Metabolism , Chaperonins Chemistry , Hsp90 Heat-Shock Proteins Chemistry Metabolism , Humans , Molecular Chaperones Chemistry , Protein Folding , Co-Chaperones , Heat Shock Protein Hsp90 , Molecular Recognition , Protein Dynamics , Protein-Protein Interaction Inhibitors
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.
Chemistry (ISSN: 0947-6539linking), 2020 Aug 3; 26 (43 ): 9459-9465.
Export to BibTeX Export to EndNote
Paper type: Journal Article
Impact factor: 0, 5-year impact factor: 0
Url: Not available.
Keywords: Carcinogens Chemistry Metabolism , Cell Cycle Proteins Chemistry Metabolism , Chaperonins Chemistry , Hsp90 Heat-Shock Proteins Chemistry Metabolism , Humans , Molecular Chaperones Chemistry , Protein Folding , Co-Chaperones , Heat Shock Protein Hsp90 , Molecular Recognition , Protein Dynamics , Protein-Protein Interaction Inhibitors
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.
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
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Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions
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Alterio V, Langella E, De Simone G, Monti SM
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The Interplay between Structural Stability and Plasticity Determines Mutation Profiles and Chaperone Dependence in Protein Kinases (37 views)
J Chem Theory Comput (ISSN: 1549-9618linking), 2018 Feb 13; 14 (2 ): 1059-1070.
Impact Factor:
View Export to BibTeX Export to EndNote
Alterio V, Langella E, De Simone G, Monti SM
* Cadmium-containing carbonic anhydrase CDCA1 in marine diatom Thalassiosira weissflogii (876 views)
Mar Drugs (ISSN: 1660-3397, 1660-3397linking), 2015 Mar 25; 13(4): 1688-1697.
Impact Factor: 3.345
View Export to BibTeX Export to EndNote
Andreotti G, Citro V, Correra A, Cubellis MV
* A thermodynamic assay to test pharmacological chaperones for Fabry disease (692 views)
Bba-Gen Subjects (ISSN: 0925-4439, 0006-3002, 1570-9639), 2014 Mar; 1840(3): 1214-1224.
Impact Factor: 4.882
View Export to BibTeX Export to EndNote
3 Records (3 excluding Abstracts).
Total impact factor: 8.227 (8.227 excluding Abstracts).
Total 5 year impact factor: 9 (9 excluding Abstracts).
Total impact factor: 8.227 (8.227 excluding Abstracts).
Total 5 year impact factor: 9 (9 excluding Abstracts).
18 views. Last view on Sunday 01 December 2024, 4:21:39
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