3HFG

Crystal Structure of Human 11-beta-hydroxysteroid-dehydrogenase Bound to an Sulfonyl-piperazine Inhibitor

3HFG の概要

• エントリーDOI: 10.2210/pdb3hfg/pdb
• 関連するPDBエントリー: 3H6K
• 分子名称: Corticosteroid 11-beta-dehydrogenase isozyme 1, (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-{[3-(1H-1,2,4-triazol-1-yl)phenyl]sulfonyl}piperazine, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, hsd1, nadp, inhibitor, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, polymorphism, signal-anchor, steroid metabolism, transmembrane
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132198.94

構造登録者

Bard, J.,Svenson, K. (登録日: 2009-05-11, 公開日: 2009-09-29, 最終更新日: 2024-02-21)

主引用文献

Wan, Z.K.,Chenail, E.,Xiang, J.,Li, H.Q.,Ipek, M.,Bard, J.,Svenson, K.,Mansour, T.S.,Xu, X.,Tian, X.,Suri, V.,Hahm, S.,Xing, Y.,Johnson, C.E.,Li, X.,Qadri, A.,Panza, D.,Perreault, M.,Tobin, J.F.,Saiah, E.
Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.
J.Med.Chem., 52:5449-5461, 2009

PubMed Abstract: Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

PubMed: 19673466
DOI: 10.1021/jm900639u

実験手法

X-RAY DIFFRACTION (2.3 Å)