3D-structure of human estrogenic 17 beta-HSD1: binding with various steroids

Human estrogenic dehydrogenase (17 beta-HSD1) catalyses the last step in th e biosynthesis of the active estrogens that stimulate the proliferation of breast cancer cells. While the primary substrate for the enzyme is estrone, the enzyme has some activity for the non-estrogenic substrates. To better understand the structure-function relationships of 17 beta-HSD1 and to prov ide a better ground for the design of inhibitors, we have determined the cr ystal structures of 17 beta-HSD1 in complex with different steroids. The st ructure of the complex of estradiol with the enzyme determined previously ( Azzi et al., Nature Structural Biology 3, 665-668) showed that the narrow a ctive site was highly complementary to the substrate. The substrate specifi city is due to a combination of hydrogen bonding and hydrophobic interactio ns between the steroid and the enzyme binding pocket. We have now determine d structures of 17 beta-HSD1 in complex with dihydrotestosterone and 20 alp ha-OH-progesterone. In the case of the C19 androgen, several residues withi n the enzyme active site make some small adjustments to accommodate the inc reased bulk of the substrate. In addition, the C19 steroids bind in a sligh tly different position from estradiol with shifts in positions of up to 1.4 Angstrom. The altered binding position avoids unfavorable steric interacti ons between Leu 149 and the C19 methyl group (Han et al., unpublished). The known kinetic parameters for these substrates can be rationalized in light of the structures presented. These results give evidence for the structura l basis of steroid recognition by 17 beta-HSD1 and throw light on the desig n of new inhibitors for this pivotal steroid enzyme. (C) 1999 Elsevier Scie nce Ltd. All rights reserved.