1J96

Human 3alpha-HSD type 3 in Ternary Complex with NADP and Testosterone

Summary for 1J96

• Entry DOI: 10.2210/pdb1j96/pdb
• Descriptor: 3alpha-hydroxysteroid dehydrogenase type 3, ACETATE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: aldo-keto reductase, steroid metabolism, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm (Potential): P52895
• Total number of polymer chains: 2
• Total formula weight: 75722.07

Authors

Nahoum, V.,Labrie, F.,Lin, S.-X. (deposition date: 2001-05-23, release date: 2002-05-23, Last modification date: 2023-08-16)

Primary citation

Nahoum, V.,Gangloff, A.,Legrand, P.,Zhu, D.W.,Cantin, L.,Zhorov, B.S.,Luu-The, V.,Labrie, F.,Breton, R.,Lin, S.X.
Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in complex with testosterone and NADP at 1.25-A resolution.
J.Biol.Chem., 276:42091-42098, 2001

PubMed Abstract: 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.

PubMed: 11514561
DOI: 10.1074/jbc.M105610200

Experimental method

X-RAY DIFFRACTION (1.25 Å)