Category: Assay Development and Screening
Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of insulin resistance, adipocyte differentiation, and inflammation. Here, we report the crystal structure of PPARγ in complex with a thiazolidinedione (TZD) class molecule with extended p-methoxyphenol moiety. The TZD moiety in the molecule 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 other agonists. However, the elongated p-methoxyphenol moiety in the molecule interacts with the hydrophobic pocket near the alternate binding site of PPARγ. The extended interaction of the TZD molecule containing p-methoxyphenol moiety with the hydrophobic pocket enhances its binding affinity and could affect the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). The phosphorylation of PPARγ at Ser245 was better inhibited by the TZD molecule with p-methoxyphenol moiety in a dose-dependent manner than a reference TZD molecule. Our study provides new structural insights into the PPARγ regulation by TZD drugs and could be useful for the discovery of new PPARγ ligands as an anti-diabetic drug, minimizing known side effects. High-throughput/automated screening of wide range of PPARγ ligands to PPARγ ligand binding domain would expedite the development of better anti-diabetic drugs with less adverse effects.
Byung Woo Han– Associate Professor, Seoul National University, Seoul, Seoul-t'ukpyolsi, Republic of Korea
Seoul National University
Seoul, Seoul-t'ukpyolsi, Republic of Korea
My lab, the Structural Pharmacy Lab at the Seoul National University, is interested in the integrative structural biology, especially in protein X-ray crystallography for the structure-function relationships of biologically important macromolecules. Our current projects are related to non-translational functions of aminoacyl-tRNA synthetases, structural analyses of tumor microenvironment-related proteins, and development of antibody alternatives.