6AD9

Crystal Structure of PPARgamma Ligand Binding Domain in complex with dibenzooxepine derivative compound-9

6AD9 の概要

• エントリーDOI: 10.2210/pdb6ad9/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, 12-mer peptide from Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, 3-[(1E)-1-{8-[(4-methyl-2-propyl-1H-benzimidazol-1-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}ethyl]-1,2,4-oxadiazol-5(4H)-one, ... (4 entities in total)
• 機能のキーワード: ppargamma ligand binding domain agonist, nuclear protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34452.02

構造登録者

Takahashi, Y.,Suzuki, M.,Yamamoto, K.,Saito, J. (登録日: 2018-07-31, 公開日: 2018-11-14, 最終更新日: 2024-03-27)

主引用文献

Yamamoto, K.,Tamura, T.,Henmi, K.,Kuboyama, T.,Yanagisawa, A.,Matsubara, M.,Takahashi, Y.,Suzuki, M.,Saito, J.I.,Ueno, K.,Shuto, S.
Development of Dihydrodibenzooxepine Peroxisome Proliferator-Activated Receptor (PPAR) Gamma Ligands of a Novel Binding Mode as Anticancer Agents: Effective Mimicry of Chiral Structures by Olefinic E/ Z-Isomers.
J. Med. Chem., 61:10067-10083, 2018

PubMed Abstract: A novel class of PPARγ ligand 1 (EC = 197 nM) with a dibenzoazepin scaffold was identified through high-throughput screening campaign. To avoid the synthetically troublesome chiral center of 1, its conformational analysis using the MacroModel was conducted, focusing on conformational flip of the tricyclic ring and the conformational restriction by the methyl group at the chiral center. On the basis of this analysis, scaffold hopping of dibenzoazepine into dibenzo[ b, e]oxepine by replacing the chiral structures with the corresponding olefinic E/ Z isomers was performed. Consequently, dibenzo[ b, e]oxepine scaffold 9 was developed showing extremely potent PPARγ reporter activity (EC = 2.4 nM, efficacy = 9.5%) as well as differentiation-inducing activity against a gastric cancer cell line MKN-45 that was more potent than any other well-known PPARγ agonists in vitro (94% at 30 nM). The X-ray crystal structure analysis of 9 complexed with PPARγ showed that it had a unique binding mode to PPARγ ligand-binding domain that differed from that of any other PPARγ agonists identified thus far.

PubMed: 30351933
DOI: 10.1021/acs.jmedchem.8b01200

実験手法

X-RAY DIFFRACTION (2.2 Å)