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 γ (PPARγ) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPARγ antagonist ligand. However, it is not well understood how imatinib binds to PPARγ or would improve insulin sensitivity without classical agonism. Here, we report the crystal structure of the PPARγ R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPARγ, of which the Arm3 region is closely related to the inhibition of PPARγ phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2′ and the Ω loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPARγ helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPARγ regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPARγ while minimizing known side effects.
Highlights
Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the thyroid hormone receptor-like nuclear receptor subfamily 1, which is one of the ligand-activated transcription factors [1]
Imatinib does not interact with Tyr473 on PPARγ helix H12, which is important for the classical agonism associated with side effects
Imatinib is a 2-phenylaminopyrimidine derivative that is chemically distinct from the thiazolidinedione (TZD) class of PPARγ full agonists (Figure 1)
Summary
Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the thyroid hormone receptor-like nuclear receptor subfamily 1, which is one of the ligand-activated transcription factors [1]. PPARγ forms a heterodimer with retinoid X receptors (RXRs), recruits coactivators, and binds to the cognate peroxisome proliferative response elements on target genes [2]. Through this process, PPARγ regulates the transcription of target genes, which plays an important role in adipocyte differentiation, lipid metabolism, glucose homeostasis, insulin sensitization, and inflammation [3,4]. As PPARγ full agonists, thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, have been widely used in treating type 2 diabetes mellitus due to their potent insulin-sensitizing effects [8]. TZDs have been prescribed with caution due to their known side effects, including weight gain, fluid retention, increased adipogenesis, and bone loss [9,10]
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