6F2L

Crystal structure of the complex between PPARgamma LBD and the ligand LJ570: structure obtained from crystals of the apo-form soaked for 15 days.

6F2L の概要

• エントリーDOI: 10.2210/pdb6f2l/pdb
• 関連するPDBエントリー: 4JL4
• 分子名称: Peroxisome proliferator-activated receptor gamma, (2S)-3-(biphenyl-4-yl)-2-(biphenyl-4-yloxy)propanoic acid (3 entities in total)
• 機能のキーワード: nuclear receptor, transcription factor, complex with an agonist, 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: 69560.27

構造登録者

Pochetti, G.,Montanari, M. (登録日: 2017-11-24, 公開日: 2018-01-10, 最終更新日: 2024-02-07)

主引用文献

Laghezza, A.,Piemontese, L.,Cerchia, C.,Montanari, R.,Capelli, D.,Giudici, M.,Crestani, M.,Tortorella, P.,Peiretti, F.,Pochetti, G.,Lavecchia, A.,Loiodice, F.
Identification of the First PPAR alpha / gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation.
J.Med.Chem., 61:8282-8298, 2018

PubMed Abstract: A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand ( S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of ( S)-6 to the canonical site. However, ( S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, ( S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.

PubMed: 30199253
DOI: 10.1021/acs.jmedchem.8b00835

実験手法

X-RAY DIFFRACTION (2.1 Å)