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-Structure paper
タイトル | Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 7010, Year 2022 |
掲載日 | 2022年11月16日 |
著者 | 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 / William Bourguet / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:36385050 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.85 - 4.07 Å |
構造データ | EMDB-14971, PDB-7zub: EMDB-14972: Cryo-EM structure of the indirubin-bound Hsp90-XAP2-AHR complex (focused map). |
化合物 | ChemComp-ADP: ChemComp-MG: ChemComp-MOO: ChemComp-JY6: |
由来 |
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キーワード | GENE REGULATION / complex / nuclear receptor / chemical pollutants / detoxification / cancer |