3H6K
Crystal Structure of Human 11-beta-hydroxysteroid-dehydrogenase Bound to an Ortho-chlro-sulfonyl-piperazine Inhibitor
Summary for 3H6K
| Entry DOI | 10.2210/pdb3h6k/pdb |
| Descriptor | Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 3-chloro-4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)benzamide, ... (4 entities in total) |
| Functional Keywords | oxidoreductase, hsd1, nadp, inhibitor, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, polymorphism, signal-anchor, steroid metabolism, transmembrane |
| Biological source | Homo sapiens (human) |
| Cellular location | Endoplasmic reticulum membrane ; Single-pass type II membrane protein : P28845 |
| Total number of polymer chains | 4 |
| Total formula weight | 132240.62 |
| Authors | Bard, J.,Svenson, K. (deposition date: 2009-04-23, release date: 2009-12-01, Last modification date: 2024-02-21) |
| Primary citation | 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 Cited by 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: 19673466DOI: 10.1021/jm900639u PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.187 Å) |
Structure validation
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