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

Min A Lee, Lingchen Tan, Huiseon Yang, Yeong-Gwan Im, Young Jun Im
2017 Scientific Reports  
Peroxisome proliferator-activator receptor (PPAR) γ is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. PPARγ 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 PPARγ
more » ... st, we determined the crystal structures of the PPARγ ligand binding domain (LBD) in complex with lobeglitazone and pioglitazone at 1.7 and 1.8 Å resolutions, respectively. Comparison of ligand-bound PPARγ 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 Ω-pocket. Docking analysis using the structures of TZD-bound PPARγ suggested that lobeglitazone displays 12 times higher affinity to PPARγ 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. Type 2 diabetes mellitus is a progressive metabolic disorder, characterized by hyperglycemia and insulin resistance in peripheral tissue. Insulin resistance is a condition in which cells fail to respond to insulin properly, causing the impaired uptake and utilization of glucose in adipose tissue and skeletal muscle 1 . Type 2 diabetes can be treated by several types of medications that increase insulin secretion by the pancreas, increase the sensitivity of target organs to insulin, reduce excessive hepatic glucose production, increase glucose utilization in the peripheral tissues, and reduce the carbohydrate absorption in the intestines 2 . Peroxisome proliferator-activated receptors (PPARs) include three subtypes: PPARα, PPARδ, and PPARγ; The PPARs are ligand-activated transcription factors that belong to the superfamily of the nuclear hormone receptors 3 . PPARs heterodimerize with the retinoid X receptor (RXR) and bind to peroxisome proliferator-response elements (PPREs), altering the transcription of target genes 4 . PPARγ which is mainly expressed in adipose tissue, liver, and skeletal muscle, regulates the genes involved in adipocyte differentiation and lipid metabolism. The endogenous ligands for PPARγ are polyunsaturated fatty acids, oxidized fatty acids, and prostaglandins 4 . Upon agonist binding, the conformation of the ligand binding domain (LBD) is altered to expose the binding cleft for the recruitment of transcriptional coactivators, which initiate the transcription of target genes 5 . Activation of PPARγ increases glucose uptake and utilization in the peripheral organs, stimulates fatty acid storage in adipocytes, enhances insulin signaling, and decreases gluconeogenesis in the liver, thereby improving insulin sensitivity 6 . Thiazolidinediones (TZDs) including pioglitazone and rosiglitazone are synthetic antihyperglycemic agents that act as PPARγ agonists 6 . TZDs enhance insulin action and improve hyperglycemia in patients with type 2 diabetes 3 . All TZDs have similar effects on glycemic control, and a range of adverse effects, such as weight gain, fluid retention, and increased risk of heart failure, which seem to be PPARγ-mediated 7 . Some adverse effects of Published: xx xx xxxx OPEN www.nature.com/scientificreports/ 2 Scientific REPORTS | 7: 16837 |
doi:10.1038/s41598-017-17082-x pmid:29203903 pmcid:PMC5715099 fatcat:mzx752xe4nfvzdm2pna3zov5ge