Structural Basis for the Enhanced Anti-Diabetic Efficacy of Lobeglitazone on PPAR gamma

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, insulin resistance, and inflammation. Here, we report the crystal structures of PPAR gamma in complex with lobeglitazone, a novel PPAR gamma agonist, and with rosiglitazone for comparison. The thiazolidinedione (TZD) moiety of lobeglitazone occupies the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i. e., helix H12) in ligand-binding domain as the TZD moiety of rosiglitazone does. However, the elongated p-methoxyphenol moiety of lobeglitazone interacts with the hydrophobic pocket near the alternate binding site of PPAR gamma. The extended interaction of lobeglitazone with the hydrophobic pocket enhances its binding affinity and could affect the cyclindependent kinase 5 (Cdk5)-mediated phosphorylation of PPAR gamma at Ser245 (in PPAR gamma 1 numbering; Ser273 in PPAR gamma 2 numbering). Lobeglitazone inhibited the phosphorylation of PPAR gamma at Ser245 in a dose-dependent manner and exhibited a better inhibitory effect on Ser245 phosphorylation than rosiglitazone did. Our study provides new structural insights into the PPAR gamma regulation by TZD drugs and could be useful for the discovery of new PPAR gamma ligands as an anti-diabetic drug, minimizing known side effects.