Steroid structure and function. Molecular conformation of 4-hydroxyestradiol and its relation to other catechol estrogens

Hydroxylation of estrogens at C(2) or C(4) effects differentially their binding affinity to and dissociation rate from the estrogen receptor. The X-ray crystal structure of 4-hydroxyestradiol (4-OH-E₂) is reported here and compared with that of 2-hydroxyestradiol (2-OH-E₂), the 2- and 4-hydroxylated derivatives of estrone (E₁) and with that of the parent estrogens, E₁ and E₂. The overall molecular shape and hydrogen bonding patterns of each were examined for their possible relevance to their binding to the estrogen receptor and their biological activity. A shift in the B-ring conformation away from the symmetrical 7α,8β -half-chair form toward the 8β-sofa form is induced by both 2- and 4-hydroxy substitution. This shift appears to be larger in the case of E₂ than E₁ derivatives and to be correlated with an observed change in the hydrogen bonding potential of the C(3) hydroxyl. In 4-OH-E₂, as in E₂ and 4-OH-E₁, the C(3) hydroxyl functions both as a hydrogen bond donor and acceptor. In contrast in 2-OH-E₂ the hydroxyl functions only as a donor. The markedly reduced affinity of 2-hydroxylated estrogens for the estrogen receptor could be due to a combination of steric interactions, competition between O(2) and O(3) for hydrogen bonds for a common site on the receptor, and to general interference with hydrogen bond formation of O(3). The C(4) hydroxyl participates in the formation of a chain of hydrogen bonds in the solid state that is similar to a chain seen in single crystals of E₂. The presence of a similar chain of hydrogen bonds involving O(3) in the receptor site could account for the decreased dissociation rate of the 4-OH-E₂ receptor complex.