Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex.
Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex.
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DOI：
10.1038/s41467-022-34773-w
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发表时间：
2022-11-16
影响因子：
16.6
通讯作者：
Bourguet, William
中科院分区：
文献类型：
--
作者：
Gruszczyk, Jakub;Grandvuillemin, Loic;Lai-Kee-Him, Josephine;Paloni, Matteo;Savva, Christos G.;Germain, Pierre;Grimaldi, Marina;Boulahtouf, Abdelhay;Kwong, Hok-Sau;Bous, Julien;Ancelin, Aurelie;Bechara, Cherine;Barducci, Alessandro;Balaguer, Patrick;Bourguet, William
芳香烃受体（aryl hydrocarbon receptor，AHR）是一种配体依赖性转录因子，对污染物、天然产物和代谢产物等多种物质的反应具有广泛的病理生理过程。然而，结构数据的缺乏阻碍了对AHR如何被这些不同化合物激活的理解。本文报道的人靛玉红结合的AHR与分子伴侣Hsp 90和共分子伴侣XAP 2的复合物的2.85 μ m结构揭示了封闭构象的Hsp 90二聚体，其中AHR穿过其内腔，XAP 2充当支架。重要的是，我们公开了期待已久的AHR PAS-B结构域的结构，揭示了配体结合口袋的独特组织和受体的配体结合特异性和混杂性的结构决定因素。通过提供导致AHR激活的分子起始事件的结构细节，我们的研究合理化了近40年的生化数据，并为未来的机制研究和结构指导的药物设计提供了框架。芳烃受体（AHR）是一种化学环境的传感器，包括污染物、食物成分和代谢产物。在这里，作者确定了靛玉红结合AHR胞质复合物的结构，为配体结合的混杂性和选择性提供了机理上的见解。
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. Aryl hydrocarbon receptor (AHR) is a sensor of the chemical environment including pollutants, diet components and metabolites. Here, authors determine the structure of the indirubin-bound AHR cytosolic complex providing mechanistic insights into ligand-binding promiscuity and selectivity.
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影响因子：
5.6
作者：
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通讯作者：
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