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.