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Vol. 273, Issue 2, 693-699, January 9, 1998
From the 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 17
Determinants of Ligand Specificity of Estrogen Receptor-
:
Estrogen versus Androgen Discrimination
,
Department of Molecular and Integrative
Physiology and the § Department of Chemistry, University of
Illinois, Urbana, Illinois 61801
-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 decreased affinity of the E353Q ER for estradiol
binding and an increased affinity for androgen binding. Therefore,
amino acid Glu353 appears to be playing a significant role
in binding the A-ring phenolic group of estradiol and in receptor
discrimination between estrogens and the most closely structurally
related steroids, androgens. Based on this data and our earlier
observations, we propose a model for the orientation of ligand within
the binding pocket of ER in which the A-ring 3-phenol of estradiol is
hydrogen bonded to Glu353 in helix-3 and the 17-hydroxyl
of estradiol is hydrogen bonded to His524 in helix-11. Our
findings with estrogen and androgen suggest that this orientation of
the steroid in the ligand-binding pocket, with the steroid A-ring in
contact with helix-3 and the D-ring in contact with helix-11 residues,
is likely to be general for all the steroid hormone receptors.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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