27-Hydroxycholesterol Is an Estrogen Receptor β-Selective Negative Allosteric Modifier of 17β-Estradiol Binding.

Abstract:

:Estrogens bind to two nuclear estrogen receptor (ER) subtypes, ERα and ERβ, which are expressed in differing amounts in various tissues. The endogenous estrogen, 17β-estradiol (E2), binds to both subtypes with nearly equal affinity and is the prototypical agonist. Selective estrogen receptor modulators (SERMs) may bind to both subtypes with equivalent affinities but have agonist activities in some tissues while having antagonist activities in others. In the present study, we demonstrate that the first reported endogenous SERM, 27-hydroxycholesterol (27-OHC), binds preferentially (>100-fold) to ERβ over ERα. Furthermore, 27-OHC is not able to fully compete with E2 binding, suggesting the two may bind at different sites. We provide an allosteric ternary complex model for the simultaneous binding of 27-OHC and E2 to ERβ, which accurately describes the binding data we have observed. We conclude that 27-OHC is a negative allosteric modifier of E2 binding, with an inhibitor constantof 50 nM and cooperativity factor (α) of 0.036. We also propose an in silico three-dimensional model of the simultaneous binding to guide future experiments. Further study of this unique binding model may allow for the discovery of novel ERβ-selective ligands and potentially explain the lack of effectiveness of ERβ-selective agonists in humans vs preclinical models.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Starkey NJE,Li Y,Drenkhahn-Weinaug SK,Liu J,Lubahn DB

doi

10.1210/en.2018-00081

subject

Has Abstract

pub_date

2018-05-01 00:00:00

pages

1972-1981

issue

5

eissn

0013-7227

issn

1945-7170

pii

4942463

journal_volume

159

pub_type

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