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

ABSTRACT: Estrogens bind to two nuclear estrogen receptor (ER) subtypes, ER? and ER?, which are expressed in differing amounts in various tissues. The endogenous estrogen, 17?-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 ER? over ER?. 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 ER?, 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 (?) 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 ER?-selective ligands and potentially explain the lack of effectiveness of ER?-selective agonists in humans vs preclinical models.

SUBMITTER: Starkey NJE

PROVIDER: S-EPMC6693046 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Starkey Nicholas J E NJE Li Yufei Y Drenkhahn-Weinaug Sara K SK Liu Jinghua J Lubahn Dennis B DB

Endocrinology 20180501 5

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 ...[more]

PMID: 29579190

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Project description:Rationale17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling.ObjectivesTo determine the mechanism by which E2 exerts protective effects in HPH.MethodsMale rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells.Measurements and main resultsE2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2-treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27(Kip1) in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.ConclusionsE2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.

Dataset Information

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

Publications

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

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