Insights into PPARγ Phosphorylation and Its Inhibition Mechanism
Year: 2020
Type: article
Abstract: PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. Synthetic antidiabetic drugs activating PPARγ are accompanied by serious undesirable side effects related to their agonism. In the search for new PPARγ regulators, inhibitors of PPARγ phosphorylation on S245 mediated by CDK5 represent an opportunity for the development of an improved generation of antidiabetic drugs acting through this nuclear receptor. We have employed a multidisciplinary approach, including protein-protein docking, X-ray crystallography, NMR, HDX, MD simulations, and site-directed mutagenesis to investigate conformational changes in PPARγ that impair the ability of CDK5 to interact with PPARγ and hence inhibit PPARγ phosphorylation. Finally, we describe an alternative inhibition mechanism adopted by a ligand bound far from the phosphorylation site.
Source: Journal of Medicinal Chemistry
Authors: Roberta Montanari, Davide Capelli, Keiko Yamamoto, Hirono Awaishima, Kimina Nishikata, Arjan Barendregt, Albert J. R. Heck, Fulvio Loiodice, Fabio Altieri, Alessandro Paiardini, Alessandro Grottesi, Luciano Pirone, Emilia Pedone, Franck Peiretti, Jean Michel Brunel, Toshimasa Itoh, Giorgio Pochetti
Institutions: Institute for Complex Systems, National Research Council, Institute of Crystallography, Showa Pharmaceutical University, Utrecht University, University of Bari Aldo Moro, Sapienza University of Rome, Cineca, Institute of Biostructure and Bioimaging, Inserm, Aix-Marseille Université, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Centre de Recherche en CardioVasculaire et Nutrition
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Award: G7557620456
OpenAlex ID: W3014576216