Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPAR gamma phosphorylation

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a major therapeutic target for the treatment of type 2 diabetes. However, the use of PPAR-gamma-targeted drugs, such as rosiglitazone and pioglitazone, is limited owing to serious side effects caused by classical agonism. Using a rational drug discovery approach, we recently developed SB1495, a novel reversible covalent inhibitor of the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of PPAR gamma at Ser245, a key factor in the insulin-sensitizing effect of PPAR-gamma-targeted drugs. In this study, we report the crystal structures of PPAR gamma in complex with SB1495 and its enantiomeric analogue SB1494, which rarely exhibits inhibitory activity, to visualize the mechanistic basis for their distinct activities. SB1495 occupies the Arm3 region near the Omega loop of the PPAR gamma ligand-binding domain, whereas its enantiomeric analogue SB1494 binds to the Arm2 region. In addition, the piperazine moiety of SB1495 directly pushes the helix H2', resulting in the stabilization of the Omega loop just behind the helix H2'. Our results may contribute to the development of a new generation of antidiabetic drugs that selectively block PPAR gamma phosphorylation without classical agonism.