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Structural characterization of the binding interactions of various endogenous estrogen metabolites with human estrogen receptor ? and ? subtypes: a molecular modeling study.

ABSTRACT: In the present study, we used the molecular docking approach to study the binding interactions of various derivatives of 17?-estradiol (E2) with human estrogen receptor (ER) ? and ?. First, we determined the suitability of the molecular docking method to correctly predict the binding modes and interactions of two representative agonists (E2 and diethylstilbesterol) in the ligand binding domain (LBD) of human ER?. We showed that the docked structures of E2 and diethylstilbesterol in the ER? LBD were almost exactly the same as the known crystal structures of ER? in complex with these two estrogens. Using the same docking approach, we then characterized the binding interactions of 27 structurally similar E2 derivatives with the LBDs of human ER? and ER?. While the binding modes of these E2 derivatives are very similar to that of E2, there are distinct subtle differences, and these small differences contribute importantly to their differential binding affinities for ERs. In the case of A-ring estrogen derivatives, there is a strong inverse relationship between the length of the hydrogen bonds formed with ERs and their binding affinity. We found that a better correlation between the computed binding energy values and the experimentally determined logRBA values could be achieved for various A-ring derivatives by re-adjusting the relative weights of the van der Waals interaction energy and the Coulomb interaction energy in computing the overall binding energy values.

SUBMITTER: Wang P

PROVIDER: S-EPMC3786999 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Structural characterization of the binding interactions of various endogenous estrogen metabolites with human estrogen receptor α and β subtypes: a molecular modeling study.

Wang Pan P McInnes Campbell C Zhu Bao Ting BT

PloS one 20130930 9

In the present study, we used the molecular docking approach to study the binding interactions of various derivatives of 17β-estradiol (E2) with human estrogen receptor (ER) α and β. First, we determined the suitability of the molecular docking method to correctly predict the binding modes and interactions of two representative agonists (E2 and diethylstilbesterol) in the ligand binding domain (LBD) of human ERα. We showed that the docked structures of E2 and diethylstilbesterol in the ERα LBD w ...[more]

PMID: 24098659

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Project description:The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

Dataset Information

Structural characterization of the binding interactions of various endogenous estrogen metabolites with human estrogen receptor ? and ? subtypes: a molecular modeling study.

Publications

Structural characterization of the binding interactions of various endogenous estrogen metabolites with human estrogen receptor α and β subtypes: a molecular modeling study.

Similar Datasets

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