Cellular and Molecular Life Sciences

, Volume 76, Issue 23, pp 4769–4781 | Cite as

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

  • Erwan Thouennon
  • Vanessa Delfosse
  • Rémy Bailly
  • Pauline Blanc
  • Abdelhay Boulahtouf
  • Marina Grimaldi
  • Alessandro Barducci
  • William BourguetEmail author
  • Patrick BalaguerEmail author
Original Article


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.


Estrogen-related receptor γ Endocrine disruptors Xenoestrogens Protein–ligand interaction 



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).

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

18_2019_3129_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1866 kb)


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institut de Recherche en Cancérologie de Montpellier (IRCM)Inserm, Univ Montpellier, ICMMontpellierFrance
  2. 2.Centre de Biochimie Structurale (CBS)Inserm, CNRS, Univ MontpellierMontpellierFrance

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