Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria km. 29.300, 00015 Monterotondo Stazione, Rome, Italy.
Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan.
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Science4Life, University of Utrecht, Padualaan 8, 3584 CH Utrecht, The Netherlands.
Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Via Orabona 4, 70125 Bari, Italy.
Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
CINECA Consorzio Interuniversitario, Sede di Roma, 00185 Rome, Italy.
Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, 80134 Naples, Italy.
Faculté de Médecine, Aix Marseille Université, INSERM, INRAE, C2VN, 13385 Marseille, France.
Aix Marseille Université, INSERM, SSA, MCT, 13385 Marseille, France.
References: Not available.
Insights into PPARγ Phosphorylation and Its Inhibition Mechanism
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.
Insights into PPARγ Phosphorylation and Its Inhibition Mechanism
Kállay C, Dávid A, Timári S, Nagy EM, Sanna D, Garribba E, Micera G, De Bona P, Pappalardo G, Rizzarelli E, Sóvágó I * Copper(II) complexes of rat amylin fragments(462 views) Dalton T (ISSN: 1477-9234, 1477-9226, 1477-9234electronic), 2011 Oct 14; 40(38): 9711-9721. Impact Factor:3.838 ViewExport to BibTeXExport to EndNote
Aloj L, Aurilio M, Rinaldi V, D'Ambrosio L, Tesauro D, Peitl PK, Maina T, Mansi R, Von Guggenberg E, Joosten L, Sosabowski JK, Breeman WA, De Blois E, Koelewijn S, Melis M, Waser B, Beetschen K, Reubi JC, De Jong M * The EEE project(532 views) Proc Int Cosm Ray Conf Icrc Universidad Nacional Autonoma De Mexico, 2007; 5(HEPART2): 977-980. Impact Factor:0 ViewExport to BibTeXExport to EndNote