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

Zdzislaw Wawrzak, William L. Duax*, Phyllis D. Strong, Judith Weisz

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    12 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)387-392
    Number of pages6
    JournalJournal of Steroid Biochemistry
    Issue number4
    StatePublished - Apr 1988

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology

    Fingerprint Dive into the research topics of 'Steroid structure and function. Molecular conformation of 4-hydroxyestradiol and its relation to other catechol estrogens'. Together they form a unique fingerprint.

    Cite this