Structural Basis for the Regulation of PPAR gamma Activity by Imatinib

Abstract

Imatinib is an effective anticancer drug for the treatment of leukemia. Interestingly, when an FDA-approved drug library was tested for agents that block peroxisome proliferator-activated receptor gamma (PPAR gamma) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPAR gamma antagonist ligand. However, it is not well understood how imatinib binds to PPAR gamma or would improve insulin sensitivity without classical agonism. Here, we report the crystal structure of the PPAR gamma R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPAR gamma, of which the Arm3 region is closely related to the inhibition of PPAR gamma phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2 ' and the Omega loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPAR gamma helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPAR gamma regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPAR gamma while minimizing known side effects.