Dehydroepiandrosterone and dihydrotestosterone recognition by human estrogenic 17 beta-hydroxysteroid dehydrogenase - C-18/C-19 steroid discrimination and enzyme-induced strain

Steroid hormones share a very similar structure, but they behave distinctly . We present structures of human estrogenic 17 beta-hydroxysteroid dehydrog enase(17 beta-HSD1) complexes with dehydroepiandrosterone (DHEA) and dihydr otestosterone (DHT), providing the first pictures to date of DHEA and DHT b ound to a protein. Comparisons of these structures with that of the enzyme complexed with the most potent estrogen, estradiol, revealed the structural basis and general model for sex hormone recognition and discrimination. Al though the binding cavity is almost entirely composed of hydrophobic residu es that can make only nonspecific interactions, the arrangement of residues is highly complementary to that of the estrogenic substrate. Relatively sm all changes in the shape of the steroid hormone can significantly affect th e binding affinity and specificity. The K-m of estrone is more than 1000-fo ld lower than that of DHEA and the K-m of estradiol is about 10 times lower than that of DHT, The structures suggest that Leu-149 is the primary contr ibutor to the discrimination of C-19 steroids and estrogens by 17 beta-HSD1 . The critical role of Leu-149 has been well confirmed by site-directed mut agenesis experiments, as the Leu-149 --> Val variant showed a significantly decreased K-m for C-19 steroids while losing discrimination between estrog ens and C-19 steroids. The electron density of DHEA also revealed a distort ion of its 17-ketone toward a beta-oriented form, which approaches the tran sition-state conformation for DHEA reduction.