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| {{STRUCTURE_3bzu| PDB=3bzu | SCENE= }} | | {{STRUCTURE_3bzu| PDB=3bzu | SCENE= }} |
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| '''Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor'''
| | ===Crystal structure of human 11-beta-hydroxysteroid dehydrogenase(HSD1) in complex with NADP and thiazolone inhibitor=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_18069989}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 18069989 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_18069989}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Steroid metabolism]] | | [[Category: Steroid metabolism]] |
| [[Category: Transmembrane]] | | [[Category: Transmembrane]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:48:00 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 14:20:59 2008'' |
