Dehydroepiandrosterone and Dihydrotestosterone Recognition by Human Estrogenic 17β-Hydroxysteroid Dehydrogenase

Abstract

Steroid hormones share a very similar structure, but they behave distinctly. We present structures of human estrogenic 17 ? -hydroxysteroid dehydrogenase (17 - ? HSD1) complexes with dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), providing the first pic- tures to date of DHEA and DHT bound to a protein. Comparisons of these structures with that of the enzyme complexed with the most potent estrogen, estradiol, re- vealed the structural basis and general model for sex hormone recognition and discrimination. Although the binding cavity is almost entirely composed of hydropho- bic residues that can make only nonspecific interac- tions, the arrangement of residues is highly complemen- tary to that of the estrogenic substrate. Relatively small changes in the shape of the steroid hormone can signif- icantly affect the binding affinity and specificity. The Km of estrone is more than 1000-fold lower than that of DHEA and the Km of estradiol is about 10 times lower than that of DHT. The structures suggest that Leu-149 is the primary contributor to the discrimination of C-19 steroids and estrogens by 17 ? -HSD1. The critical role of Leu-149 has been well confirmed by site-directed mu- tagenesis experiments, as the Leu-149 3 Val variant showed a significantly decreased Km for C-19 steroids while losing discrimination between estrogens and C-19 steroids. The electron density of DHEA also revealed a distortion of its 17-ketone toward a ? -oriented form, which approaches the transition-state conformation for DHEA