The mechanism of action of steroid antagonists: Insights from crystallographic studies

W. L. Duax*, J. F. Griffin, C. M. Weeks, Z. Wawrzak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Examination of the structures of compounds having high affinity for estrogen, progestin, mineralocorticoid and glucocorticoid receptors strongly suggests that receptor binding is primarily the result of a tight association between the receptor and the steroidal A-ring. High affinity binding to the estrogen receptor appears to be dependent upon the presence of a phenolic ring in the substrate. An inverted 1β,2α conformation of the 4-ene-3-one A-ring appears to be most conducive to high affinity binding to the progesterone receptor. Binding to the mineralocorticoid receptor appears to be correlated to a complementary fit between amino acids of the receptor site and a flat 4-en-3-one A-ring similar to that imposed upon aldosterone by the 11,18-epoxide formation. The glucocorticoid receptor appears to prefer a 4-en-3-one A-ring that is bowed toward the α-face as is the case in structures having a 9α-fluoro substituent or additional unsaturation at C(1)-C(2). The binding of androgens to their receptor differs in appearing to have an essential dependence upon functional groups at the A- and D-ring end of the steroid. With the exception of the androgens, the data suggest that specific interactions between the steroid B-, C- and D-rings and the receptor play at best a minor role in receptor binding but are the most important factor in determining agonist versus antagonist behavior subsequent to binding. Antagonists that compete for a steroid receptor site may be expected to have the A-ring composition and conformation necessary for receptor binding but lack the 11β-OH and the D-ring conformational features and functional groups that induce or stabilize subsequent receptor functions. Antagonists might also be compounds with A-ring conformations appropriate for binding but other structural features that interfere with subsequent receptor functions essential to activity.

Original languageEnglish (US)
Pages (from-to)481-492
Number of pages12
JournalJournal of Steroid Biochemistry
Issue number4
StatePublished - Jan 1 1988

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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