5Y2O

Structure of PPARgamma ligand binding domain-pioglitazone complex

5Y2O の概要

• エントリーDOI: 10.2210/pdb5y2o/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, (5S)-5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione (3 entities in total)
• 機能のキーワード: ppargamma, nuclear receptor, pioglitazone, thiazolidinedione, ligand binding domain, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: P37231
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67109.69

構造登録者

Im, Y.J.,Lee, M. (登録日: 2017-07-26, 公開日: 2017-12-20, 最終更新日: 2023-11-22)

主引用文献

Lee, M.A.,Tan, L.,Yang, H.,Im, Y.G.,Im, Y.J.
Structures of PPAR gamma complexed with lobeglitazone and pioglitazone reveal key determinants for the recognition of antidiabetic drugs
Sci Rep, 7:16837-16837, 2017

PubMed Abstract: 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 agonist, 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.

PubMed: 29203903
DOI: 10.1038/s41598-017-17082-x

実験手法

X-RAY DIFFRACTION (1.801 Å)