2I4Z

Crystal structure of the complex between PPARgamma and the partial agonist LT127 (ureidofibrate derivative). This structure has been obtained from crystals soaked for 6 hours.

2I4Z の概要

• エントリーDOI: 10.2210/pdb2i4z/pdb
• 関連するPDBエントリー: 1PRG 2I4J 2PRG 4PRG
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2S)-2-(4-{2-[1,3-BENZOXAZOL-2-YL(HEPTYL)AMINO]ETHYL}PHENOXY)-2-METHYLBUTANOIC ACID (3 entities in total)
• 機能のキーワード: bundle of alpha-helices and a small four-stranded beta-sheet, 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: 65513.89

構造登録者

Pochetti, G.,Mazza, F. (登録日: 2006-08-23, 公開日: 2007-04-17, 最終更新日: 2023-08-30)

主引用文献

Pochetti, G.,Godio, C.,Mitro, N.,Caruso, D.,Galmozzi, A.,Scurati, S.,Loiodice, F.,Fracchiolla, G.,Tortorella, P.,Laghezza, A.,Lavecchia, A.,Novellino, E.,Mazza, F.,Crestani, M.
Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands
J.Biol.Chem., 282:17314-17324, 2007

PubMed Abstract: The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also targets of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate-like derivatives. In particular, we show that the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the S-enantiomer, (S)-1, is a less potent partial agonist. Most importantly, we report the x-ray crystal structures of the PPARgamma ligand binding domain complexed with the R- and the S-enantiomer, respectively. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behavior as full or partial agonist. Another crystal structure of the PPARgamma.(S)-1 complex, only differing in the soaking time of the ligand, is also presented. The comparison of the two structures of the complexes with the partial agonist reveals significant differences and is suggestive of the possible coexistence in solution of transcriptionally active and inactive forms of helix 12 in the presence of a partial agonist. Mutation analysis confirms the importance of Leu(465), Leu(469), and Ile(472) in the activation by (R)-1 and underscores the key role of Gln(286) in the PPARgamma activity.

PubMed: 17403688
DOI: 10.1074/jbc.M702316200

実験手法

X-RAY DIFFRACTION (2.25 Å)