Structures of PPARγ complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs

Peroxisome proliferator-activator receptor (PPAR) gamma is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. PPAR gamma is a target for thiazolidinedione (TZD) class of drugs which are widely used for the treatment of type 2 diabetes. Recently, lobeglitazone was developed as a highly effective TZD with reduced side effects by Chong Kun Dang Pharmaceuticals. To identify the structural determinants for the high potency of lobeglitazone as a PPAR gamma agonist, we determined the crystal structures of the PPAR gamma ligand binding domain (LBD) in complex with lobeglitazone and pioglitazone at 1.7 and 1.8 angstrom resolutions, respectively. Comparison of ligand-bound PPAR gamma structures revealed that the binding modes of TZDs are well conserved. The TZD head group forms hydrogen bonds with the polar residues in the AF-2 pocket and helix 12, stabilizing the active conformation of the LBD. The unique p-methoxyphenoxy group of lobeglitazone makes additional hydrophobic contacts with the Omega-pocket. Docking analysis using the structures of TZD-bound PPAR gamma suggested that lobeglitazone displays 12 times higher affinity to PPAR gamma compared to rosiglitazone and pioglitazone. This structural difference correlates with the enhanced affinity and the low effective dose of lobeglitazone compared to the other TZDs.