5HZC

Crystal structure of the complex PPARgamma/AL26-29

5HZC の概要

• エントリーDOI: 10.2210/pdb5hzc/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, 2-methyl-2-[4-(naphthalen-1-yl)phenoxy]propanoic acid (3 entities in total)
• 機能のキーワード: nuclear receptor, transcription factor, diabetes, bundle of alpha-helices, 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: 66000.36

構造登録者

Pochetti, G.,Montanari, R.,Capelli, D.,Loiodice, F.,Laghezza, A.,Lavecchia, A. (登録日: 2016-02-02, 公開日: 2016-11-23, 最終更新日: 2024-01-10)

主引用文献

Capelli, D.,Cerchia, C.,Montanari, R.,Loiodice, F.,Tortorella, P.,Laghezza, A.,Cervoni, L.,Pochetti, G.,Lavecchia, A.
Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode.
Sci Rep, 6:34792-34792, 2016

PubMed Abstract: The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

PubMed: 27708429
DOI: 10.1038/srep34792

実験手法

X-RAY DIFFRACTION (2 Å)