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Role of pocket flexibility in the modulation of estrogen receptor alpha by key residue arginine 394

Authors

  • Yunsong Mu,

    1. State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing, China
    2. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Chinese Academy of Sciences, Beijing, China
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  • Sufen Peng,

    1. State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing, China
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  • Aiqian Zhang,

    Corresponding author
    1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Chinese Academy of Sciences, Beijing, China
    • State Key Laboratory of Environmental Chemistry and Ecotoxicology, Chinese Academy of Sciences, Beijing, China.
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  • Liansheng Wang

    1. State Key Laboratory of Pollution Control and Resource Reuse, Nanjing University, Nanjing, China
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Abstract

Estradiol derivatives, with similar structures as estradiol (E2) or estradiol metabolites, have been recognized to have detrimental health effects on wildlife and humans. However, data at the molecular level about interactions of these compounds with biological targets are still lacking. Herein, a flexible docking approach was used to characterize the molecular interaction of nine estradiol derivatives with estrogen receptor alpha (ERα) in the ligand-binding domain. All ligands were docked in the buried hydrophobic cavity of the steroid hormone pocket. In addition, the plasticity of an active site was also identified by reversing amino acid arginine 394 for better ligand-receptor binding affinity. Finally, bioassays based on genetically modified yeast strains were used to validate the quality of molecular simulation because of their rapidity and high sensitivity. The experimental findings about logarithm values of the median effective concentration (EC50) value had a linear correlation with computational binding affinity from molecular docking, which described a pattern of interaction between estradiol derivatives and ER. The estrogenic activity of all compounds, although more or less lower than E2, was proved to possess high severe environmental risks. Considering the sidechain flexibility in the ligand binding pocket, 17α-ethylestradiol-3-cyclopentylether was reported to correlate highly significantly with known induced fit conformational changes based upon proof-of-principle calculations on human ERα with the preservation of a strong salt bridge between glutamic acid 353 and arginine 394. Environ. Toxicol. Chem. 2011;30:330–336. © 2010 SETAC

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