Speaker
Description
Peroxisome proliferator-activated receptor gamma Ligand Binding Domain (PPARγ-LBD) represents a key
target for the treatment of type II diabetes and metabolic syndrome. This receptor is the target of
thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in
type 2 diabetes. Unfortunately, despite the beneficial effects of synthetic drugs, their use is associated with
serious undesirable side effects1,2 related to their agonism. By contrast, a promising activation-independent
mechanism that involves the inhibition of cyclin-dependent kinase 5 (Cdk5)-mediated PPARγ
phosphorylation (CMPF) has been related to the insulin-sensitizing effects induced by these drugs3,4. For this
reason, the search for new inhibitors of CMPF represents an opportunity for the development of an improved
generation of anti-diabetic drugs acting through this nuclear receptor. Thus, with the aim to identify novel
drug-like inhibitors of CMPF capable of interacting with PPARγ but that lack agonist properties we adopted
a multi-disciplinary approach, including protein-protein docking, X-ray, NMR, HDX, MD simulations and
site-directed mutagenesis to investigate conformational changes in PPARγ that impair the ability of Cdk5 to
interact with this nuclear receptor and hence inhibit its phosphorylation.
