
<ArticleTitle>Crystal structure of human <prot>type III 3alpha-hydroxysteroid dehydrogenase</prot>/<prot>bile acid binding protein</prot> complexed with NADP(+) and ursodeoxycholate.</ArticleTitle>
<AbstractText>The crystal structure of human <prot>type III 3alpha-hydroxysteroid dehydrogenase</prot> (<prot>HSD</prot>)/<prot>bile acid binding protein</prot> (<prot>AKR1C2</prot>) complexed with NADP(+) and 3alpha,7beta-dihydroxy-5beta-cholanic acid (ursodeoxycholate) at 3.0 A resolution is presented. Thus, the three-dimensional structure has now been solved for a human <prot>HSD</prot> member of the aldo-keto reductase superfamily. <prot>AKR1C2</prot> is implicated in the prostatic production of the potent androgen 5alpha-dihydrotestosterone and the hepatic transport of bile acids. It also catalyzes the formation of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in the central nervous system, and its allosteric modulation by fluoxetine has been linked to the use of this drug for premenstrual dsyphoria. Like other members of the superfamily, <prot>AKR1C2</prot> folds into an alpha/beta-barrel and binds NADP(+) in an extended conformation. The carboxylate of ursodeoxycholate binds to <prot>AKR1C2</prot> in the oxyanion hole at the active site. More interestingly, the orientation of ursodeoxycholate is essentially "backwards" and "upside-down" from that observed for testosterone in the related rat <prot>3alpha-HSD</prot>.NADP(+).testosterone ternary complex, where testosterone assumes the position of a 3-ketosteroid substrate. The orientation of ursodeoxycholate is thus similar to that expected of a 17beta-HSD substrate. The ternary structure explains the ability of <prot>AKR1C2</prot> to catalyze 3alpha-, 17beta-, and 20alpha-HSD reactions. Comparison of the steroid binding pocket of <prot>AKR1C2</prot> with that of rat <prot>3alpha-HSD</prot> reveals significant differences in the positions of conserved and nonconserved loop residues, providing insights into the structural basis for the functional flexibility that is observed in all the human <prot>3alpha-HSD</prot> isoforms but not in the rat isoform.</AbstractText>
