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

Gruszczyk, J.; Grandvuillemin, L.; Lai-Kee-Him, J.; Paloni, M.; Savva, C. G.; Germain, P.; Grimaldi, M.; Boulahtouf, A.; Kwong, H.-S.; Bous, J.; Ancelin, A.; Bechara, C.; Barducci, A.; Balaguer, P.; Bourguet, W.

doi:10.1101/2022.05.17.491947

bioRxiv · 10.1101/2022.05.17.491947

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

Gruszczyk, J.·Grandvuillemin, L.·Lai-Kee-Him, J.·Paloni, M.·Savva, C. G.·Germain, P.·Grimaldi, M.·Boulahtouf, A.·Kwong, H.-S.·Bous, J.·Ancelin, A.·Bechara, C.·Barducci, A.·Balaguer, P.·Bourguet, W.

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Abstract

SummaryLiving organisms have developed protein sensors helping them to adapt to their environment1. The aryl hydrocarbon receptor (AHR) is an emblematic member of this class of proteins, and a ligand-dependent transcription factor that mediates a broad spectrum of (patho)physiological processes in response to numerous substances including pollutants, natural products and metabolites2. However, in the absence of high-resolution structural data, a molecular understanding of how AHR is activated by such diverse compounds is lacking. Here we present a 2.85 [A] cryo-electron microscopy structure of the cytosolic complex comprising AHR bound to the ligand indirubin, the chaperone Hsp90 and the co-chaperone XAP2. The structure reveals a closed Hsp90 dimer with AHR threaded through its lumen. XAP2 directly interacts with Hsp90 and the AHR ligand-binding domain, thereby acting as a brace stabilizing the entire complex. Importantly, we provide the first experimental visualization of the AHR PAS-B domain bound to a ligand, revealing a unique organization of the ligand-binding pocket and the structural determinants of ligand-binding specificity and promiscuity of the receptor. By providing unprecedented structural details of the molecular initiating event leading to AHR activation, our study rationalizes prior biochemical data and provides a framework for future mechanistic studies and structure-guided drug design.

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Gruszczyk, J., Grandvuillemin, L., Lai-Kee-Him, J., Paloni, M., Savva, C. G., Germain, P., Grimaldi, M., Boulahtouf, A., Kwong, H.-S., Bous, J., Ancelin, A., Bechara, C., Barducci, A., Balaguer, P., Bourguet, W.. 2022-05-17. Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR complex. https://doi.org/10.1101/2022.05.17.491947

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