3BZU

Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor

Summary for 3BZU

• Entry DOI: 10.2210/pdb3bzu/pdb
• Related: 1xu9
• Descriptor: Corticosteroid 11-beta-dehydrogenase isozyme 1, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (5S)-2-{[(1S)-1-(2-fluorophenyl)ethyl]amino}-5-methyl-5-(trifluoromethyl)-1,3-thiazol-4(5H)-one, ... (4 entities in total)
• Functional Keywords: 11beta hydroxysteroid dehydrogenase, endoplasmic reticulum, glycoprotein, lipid metabolism, membrane, microsome, nadp, oxidoreductase, 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: 131602.34

Authors

Min, X.,Sudom, A.,Xu, H.,Wang, Z.,Walker, N.P. (deposition date: 2008-01-18, release date: 2008-06-10, Last modification date: 2024-02-21)

Primary citation

Hale, C.,Veniant, M.,Wang, Z.,Chen, M.,McCormick, J.,Cupples, R.,Hickman, D.,Min, X.,Sudom, A.,Xu, H.,Matsumoto, G.,Fotsch, C.,St Jean, D.J.,Wang, M.
Structural characterization and pharmacodynamic effects of an orally active 11beta-hydroxysteroid dehydrogenase type 1 inhibitor.
Chem.Biol.Drug Des., 71:36-44, 2008

PubMed Abstract: 11Beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid action and inhibition of this enzyme is a viable therapeutic strategy for the treatment of type 2 diabetes and the metabolic syndrome. Here, we report a potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor with a binding mode elucidated from the co-crystal structure with the human 11beta-hydroxysteroid dehydrogenase type 1. The inhibitor is bound to the steroid-binding pocket making contacts with the catalytic center and the solvent channel. The inhibitor binding is facilitated by two direct hydrogen bond interactions involving Tyrosine183 of the catalytic motif Tyr-X-X-X-Lys and Alanine172. In addition, the inhibitor makes many hydrophobic interactions with both the enzyme and the co-factor nicotinamide adenine dinucleotide phosphate (reduced). In lean C57BL/6 mice, the compound inhibited both the in vivo and ex vivo 11beta-hydroxysteroid dehydrogenase type 1 activities in a dose-dependent manner. The inhibitory effects correlate with the plasma compound concentrations, suggesting that there is a clear pharmacokinetic and pharmacodynamic relationship. Moreover, at the same doses used in the pharmacokinetic/pharmacodynamic studies, the inhibitor did not cause the activation of the hypothalamic-pituitary-adrenal axis in an acute mouse model, suggesting that this compound exhibits biological effects with minimal risk of activating the hypothalamic-pituitary-adrenal axis.

PubMed: 18069989
DOI: 10.1111/j.1747-0285.2007.00603.x

Experimental method

X-RAY DIFFRACTION (2.25 Å)