Determinants of ligand specificity of estrogen receptor-alpha: estrogen versus androgen discrimination.

The Journal of Biological Chemistry
K EkenaB S Katzenellenbogen

Abstract

We have been interested in understanding how the estrogen receptor (ER) binds estrogens and discriminates between different classes of steroids with closely related structures. Using insights from our prior studies on ER and from sequence comparisons of steroid receptors, we identified three residues in the hormone-binding domain of the human ER, Leu345, Thr347, and Glu353, that we considered were likely to be involved in steroid A-ring recognition and therefore estrogen versus androgen discrimination. We then tested the effect on ER activity of mutating these ER residues to the corresponding androgen receptor residues. Specifically, we examined the ability of the mutant receptors to bind and be activated by 17beta-estradiol and three different androgens. No change in receptor activity was observed with the T347N mutation, while the L345S mutation greatly reduced ER activity in response to all ligands. Interestingly, the E353Q substitution behaved as expected, causing a 9-fold reduction in the transactivation potency of estradiol and a concomitant 10-140-fold increase in the transactivation potency of different androgens. These reciprocal changes in the transcriptional effectiveness of estrogens and androgens correlated with a ...Continue Reading

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