Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex

Jakub Gruszczyk (), Loïc Grandvuillemin, Josephine Lai-Kee-Him, Matteo Paloni, Christos G. Savva, Pierre Germain, Marina Grimaldi, Abdelhay Boulahtouf, Hok-Sau Kwong, Julien Bous, Aurélie Ancelin, Cherine Bechara, Alessandro Barducci, Patrick Balaguer and William Bourguet ()
Additional contact information
Jakub Gruszczyk: Univ Montpellier, CNRS, Inserm
Loïc Grandvuillemin: Univ Montpellier, CNRS, Inserm
Josephine Lai-Kee-Him: Univ Montpellier, CNRS, Inserm
Matteo Paloni: Univ Montpellier, CNRS, Inserm
Christos G. Savva: University of Leicester
Pierre Germain: Univ Montpellier, CNRS, Inserm
Marina Grimaldi: Univ Montpellier, ICM
Abdelhay Boulahtouf: Univ Montpellier, ICM
Hok-Sau Kwong: Univ Montpellier, CNRS, Inserm
Julien Bous: Karolinska Institutet
Aurélie Ancelin: Univ Montpellier, CNRS, Inserm
Cherine Bechara: IGF, University of Montpellier, CNRS, Inserm
Alessandro Barducci: Univ Montpellier, CNRS, Inserm
Patrick Balaguer: Univ Montpellier, ICM
William Bourguet: Univ Montpellier, CNRS, Inserm

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites. However, the scarcity of structural data precludes understanding of how AHR is activated by such diverse compounds. Our 2.85 Å structure of the human indirubin-bound AHR complex with the chaperone Hsp90 and the co-chaperone XAP2, reported herein, reveals a closed conformation Hsp90 dimer with AHR threaded through its lumen and XAP2 serving as a brace. Importantly, we disclose the long-awaited structure of the AHR PAS-B domain revealing a unique organisation of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing structural details of the molecular initiating event leading to AHR activation, our study rationalises almost forty years of biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.

Date: 2022
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DOI: 10.1038/s41467-022-34773-w

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