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Insights into the activation mechanism of human estrogen-related receptor γ by environmental endocrine disruptors

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Abstract

The estrogen-related receptor γ (ERRγ, NR3B3) is a constitutively active nuclear receptor which has been proposed to act as a mediator of the low-dose effects of a number of environmental endocrine-disrupting chemicals (EDCs) such as the xenoestrogen bisphenol-A (BPA). To better characterize the ability of exogenous compounds to bind and activate ERRγ, we used a combination of cell-based, biochemical, structural and computational approaches. A purposely created stable cell line allowed for the determination of the EC50s for over 30 environmental ERRγ ligands, including previously unknown ones. Interestingly, affinity constants (Kds) of the most potent compounds measured by isothermal titration calorimetry were in the 50–500 nM range, in agreement with their receptor activation potencies. Crystallographic analysis of the interaction between the ERRγ ligand-binding domain (LBD) and compounds of the bisphenol, alkylphenol and naphthol families revealed a partially shared binding mode and minimal alterations of the receptor conformation upon ligand binding. Further biophysical characterizations coupled to molecular dynamics simulations suggested a mechanism through which ERRγ ligands would exhibit their agonistic properties by preserving the transcriptionally active form of the receptor while rigidifying some loop regions with associated functions. This unique mechanism contrasts with the classical one involving a ligand-induced repositioning and stabilization of the C-terminal activation helix H12.

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Acknowledgements

The CBS is a member of the France-BioImaging (FBI) and the French Infrastructure for Integrated Structural Biology (FRISBI), two national infrastructures supported by the French National Research Agency (ANR-10-INBS-04-01 and ANR-10-INBS-05, respectively). We acknowledge the experimental assistance from the staff of the European Synchrotron Radiation Facility (ESRF, Grenoble, France) during data collection. We would like to acknowledge the financial support from the Plan Cancer Inserm, project CONTERREC C16007FS (PB and WB) and the French Agence Nationale de la Recherche, under grants ANR-13-CESA-0012-04 (PB) and ANR-14-ACHN-0016 (AB).

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  1. Erwan Thouennon and Vanessa Delfosse share the first authorship.

  2. William Bourguet and Patrick Balaguer share the last authorship.

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  1. Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm, Univ Montpellier, ICM, Montpellier, France

    Erwan Thouennon, Abdelhay Boulahtouf, Marina Grimaldi & Patrick Balaguer

  2. Centre de Biochimie Structurale (CBS), Inserm, CNRS, Univ Montpellier, Montpellier, France

    Vanessa Delfosse, Rémy Bailly, Pauline Blanc, Alessandro Barducci & William Bourguet

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  1. Erwan Thouennon
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Thouennon, E., Delfosse, V., Bailly, R. et al. Insights into the activation mechanism of human estrogen-related receptor γ by environmental endocrine disruptors. Cell. Mol. Life Sci. 76, 4769–4781 (2019). https://doi.org/10.1007/s00018-019-03129-x

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