Steroid structure and function-IX. molecular conformation of catechol estrogens

William L. Duax, Jane F. Griffin, Dale C. Swenson, Phyllis D. Strong, Judith Weisz

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The catechol estrogens have varying degrees of affinity for the estrogen receptor, catecholamine enzymes and the dopamine receptor. The X-ray crystal structures of 2-hydroxyestradiol, 2-hydroxyestrone and 4-hydroxyestrone are reported here and compared with those of estradiol, estrone, dopamine and apomorphine. The overall molecular shapes and hydrogen bonding patterns have been examined for possible relevance to protein binding and activity. The principal structural observations and their potential significance are the following: (1) The 4-hydroxyestrone results indicate that the 4-substituent does not constitute a steric impediment to estrogen receptor binding but does restrict the probable location of the hydrogen bond acceptor atom on the receptor. (2) The reduced affinity of 2-hydroxyestradiol for the estrogen receptor may be due to a combination of steric interaction and interference with hydrogen bond formation of O(3). (3) The reduced affinity of 17-one substituted steroids in this series for the estrogen receptor most strongly supports the probable importance of a hydrogen bond donor at that position interacting directly with the receptor. (4) In the catechol estrogens the formation of an intramolecular and two or more intermolecular hydrogen bonds together with the extension of the A ring's planar surface to include the hydroxyl substituents and part of the B ring must account for its high binding affinity for catechol amine related enzymes, the dopamine receptor and a putative catechol estrogen receptor. (5) Two orientations of the catechol estrogens relative to that of dopamine when bound to its receptor are suggested by this study. One achieves maximum overlap of the hydrogen bond pattern of the dihydroxy benzene ring and the other maximizes similarity in overall shape. The results of this investigation are consistent with the hypothesis that the A-ring plays a primary role in initiating estrogen binding to its receptor and suggests an even more highly specific A-ring interaction with the dopamine receptor and catechol amine enzymes.

Original languageEnglish (US)
Pages (from-to)263-271
Number of pages9
JournalJournal of Steroid Biochemistry
Volume18
Issue number3
DOIs
StatePublished - Mar 1983

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology

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