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Endocrinology Vol. 141, No. 10 3534-3545
Copyright © 2000 by The Endocrine Society

ARTICLES

Conformational Changes and Coactivator Recruitment by Novel Ligands for Estrogen Receptor-{alpha} and Estrogen Receptor-ß: Correlations with Biological Character and Distinct Differences among SRC Coactivator Family Members1

Dennis M. Kraichely, Jun Sun, John A. Katzenellenbogen and Benita S. Katzenellenbogen

Departments of Molecular and Integrative Physiology (D.M.K., J.S., B.S.K.), Cell and Structural Biology (B.S.K.), and Chemistry (J.A.K.), University of Illinois and College of Medicine, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, University of Illinois, Urbana, Illinois 61801-3704. E-mail: katzenel{at}life.uiuc.edu

Ligands for the estrogen receptor (ER) that have the capacity to selectively bind to or activate the ER subtypes ER{alpha} or ERß would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. In this study, we examine three compounds of novel structure that act as ER subtype-selective ligands. These are a propyl pyrazole triol (PPT), which is a potent agonist on ER{alpha} but is inactive on ERß, and a pair of substituted tetrahydrochrysenes (THC), one enantiomer of which (S,S-THC) is an agonist on both ER{alpha} and ERß, the other (R,R-THC) being an agonist on ER{alpha} but an antagonist on ERß. To investigate the molecular mechanisms underlying the ER subtype-selective actions of these compounds, we have determined the conformational changes induced in ER{alpha} and ERß by these ligands using protease digestion sensitivity, and we have tested the ability of these ligands to promote the recruitment of representatives of the three SRC/p160 coactivator protein family members (SRC-1, GRIP-1, ACTR, respectively) to ER{alpha} and ERß using yeast two-hybrid and glutathione-S-transferase (GST) pull-down assays. We find that the ligand-ER protease digestion pattern is distinctly different for stimulatory and inhibitory ligands, and that this assay, as well as coactivator recruitment, are excellent indicators of their agonist/antagonist character. Interestingly however, compared with estradiol, the novel agonist ligands show some quantitative differences in their ability to recruit SRC-1, -2, and -3. This implies that while generally similar to estradiol, these ligands induce ER conformations that differ somewhat from that induced by estradiol, differences that are illustrative of the nature of their biological character. The application of methods to characterize the conformations induced in ER subtypes by novel ligands, as done in this study, enables a greater understanding of how ligand-receptor conformations relate to estrogen agonist or antagonist behavior.




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