4E4K

Crystal Structure of PPARgamma with the ligand JO21

4E4K の概要

• エントリーDOI: 10.2210/pdb4e4k/pdb
• 関連するPDBエントリー: 3B3K 3K8S 4E4Q
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2S)-3-phenyl-2-{[2'-(propan-2-yl)biphenyl-4-yl]oxy}propanoic 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 factor, 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: 66108.54

構造登録者

Pochetti, G.,Montanari, R.,Loiodice, F.,Fracchiolla, G.,Laghezza, A.,Carbonara, G.,Piemontese, L.,Lavecchia, A.,Novellino, E. (登録日: 2012-03-13, 公開日: 2013-01-23, 最終更新日: 2024-02-28)

主引用文献

Laghezza, A.,Pochetti, G.,Lavecchia, A.,Fracchiolla, G.,Faliti, S.,Piemontese, L.,Di Giovanni, C.,Iacobazzi, V.,Infantino, V.,Montanari, R.,Capelli, D.,Tortorella, P.,Loiodice, F.
New 2-(Aryloxy)-3-phenylpropanoic Acids as Peroxisome Proliferator-Activated Receptor alpha/gamma Dual Agonists Able To Upregulate Mitochondrial Carnitine Shuttle System Gene Expression.
J.Med.Chem., 56:60-72, 2013

PubMed Abstract: The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor α/γ (PPARα/γ) dual agonist 1, allowed the identification of new ligands with higher potency on PPARα and fine-tuned moderate PPARγ activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARγ revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARα and PPARγ, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARα agonist fibrates currently used in therapy.

PubMed: 23171045
DOI: 10.1021/jm301018z

実験手法

X-RAY DIFFRACTION (2.5 Å)