1j96
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(New page: 200px<br /> <applet load="1j96" size="450" color="white" frame="true" align="right" spinBox="true" caption="1j96, resolution 1.25Å" /> '''Human 3alpha-HSD ty...)
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Revision as of 15:32, 12 November 2007
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Human 3alpha-HSD type 3 in Ternary Complex with NADP and Testosterone
Contents |
Overview
The first crystallographic structure of human type 3 3alpha-hydroxysteroid, dehydrogenase (3alpha-HSD3, AKR1C2), an enzyme playing a critical role in, steroid hormone metabolism, has been determined in complex with, testosterone and NADP at 1.25-A resolution. The enzyme's 17beta-HSD, activity was studied in comparison with its 3alpha-HSD activity. The, enzyme catalyzes the inactivation of dihydrotestosterone into, 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) as well as the, transformation of androstenedione into testosterone. Using our homogeneous, and highly active enzyme preparation, we have obtained 150-fold higher, 3alpha-HSD specificity as compared with the former reports in the, literature. Although the rat and the human 3alpha-HSDs share 81% sequence, homology, our structure reveals significantly different geometries of the, active sites. Substitution of the Ser(222) by a histidine in the human, enzyme may compel the steroid to adopt a different binding to that, previously described for the rat (Bennett, M. J., Albert, R. H., Jez, J., M., Ma, H., Penning, T. M., and Lewis, M. (1997) Structure 5, 799-T812)., Furthermore, we showed that the affinity for the cofactor is higher in the, human 3alpha-HSD3 than the rat enzyme due to the presence of additional, hydrogen bonds on the adenine moiety and that the cofactor is present, under its reduced form in the active site in our preparation.
Disease
Known diseases associated with this structure: Obesity, hyperphagia, and developmental delay OMIM:[600450]
About this Structure
1J96 is a Single protein structure of sequence from Homo sapiens with ACT, NAP and TES as ligands. Active as 3-alpha-hydroxysteroid dehydrogenase (A-specific), with EC number 1.1.1.213 Full crystallographic information is available from OCA.
Reference
Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution., Nahoum V, Gangloff A, Legrand P, Zhu DW, Cantin L, Zhorov BS, Luu-The V, Labrie F, Breton R, Lin SX, J Biol Chem. 2001 Nov 9;276(45):42091-8. Epub 2001 Aug 20. PMID:11514561
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