3IA6

X-ray Crystal structure of the nuclear hormone receptor PPAR-gamma in a complex with a PPAR gamma/alpha dual agonist

3IA6 の概要

• エントリーDOI: 10.2210/pdb3ia6/pdb
• 関連するPDBエントリー: 2Q8S
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2S)-3-{4-[3-(5-methyl-2-phenyl-1,3-oxazol-4-yl)propyl]phenyl}-2-(2H-1,2,3-triazol-2-yl)propanoic acid (3 entities in total)
• 機能のキーワード: protein-ligand complex, dual specificity, inhibitor, activator, alternative splicing, diabetes mellitus, disease mutation, dna-binding, metal-binding, nucleus, obesity, phosphoprotein, polymorphism, receptor, transcription, transcription regulation, zinc, zinc-finger
• 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: 62826.99

構造登録者

Ohren, J.F. (登録日: 2009-07-13, 公開日: 2009-10-13, 最終更新日: 2023-09-06)

主引用文献

Casimiro-Garcia, A.,Bigge, C.F.,Davis, J.A.,Padalino, T.,Pulaski, J.,Ohren, J.F.,McConnell, P.,Kane, C.D.,Royer, L.J.,Stevens, K.A.,Auerbach, B.,Collard, W.,McGregor, C.,Song, K.
Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists.
Bioorg.Med.Chem., 17:7113-7125, 2009

PubMed Abstract: The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.

PubMed: 19783444
DOI: 10.1016/j.bmc.2009.09.001

実験手法

X-RAY DIFFRACTION (2.31 Å)