Cryo-EM structure of the cytosolic AhR complex

Wen, Zuoling; Zhang, Yuebin; Zhang, Beirong; Hang, Yumo; Xu, Li; Chen, Yangsheng; Xie, Qiaorong; Zhao, Qun; Zhang, Lihua; Li, Guohui; Zhao, Bin; Sun, Fei; Zhai, Yujia; Zhu, Yun

doi:10.1016/j.str.2022.12.013

Cited by 19 publications

(7 citation statements)

References 57 publications

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“…The average cavity volume (356 Ȧ 3 ) within the human AHR PAS-B (PDB 7ZUB 27 ) remained similar to the ligand filled state (382 Ȧ 3 ). This lack of response was confirmed by running a simulation of the empty structure from the murine AHR (PDB 8H77, 44 cavity 380 Ȧ 3 ). In contrast, when emptied of JH III, the GCE PAS-B model reduced its average cavity volume from 522 to 290 Ȧ 3 .…”

Section: Resultsmentioning

confidence: 86%

“…While experimental data for T289 mutagenesis are unavailable for human AHR, T283M mutation of the equivalent residue within murine AHR (mAHR) has been shown to abolish binding of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). 42,43 Indeed, Figure S1 shows that in silico mutation and MD simulation in a mAHR PAS-B model that was based on a cryo-EM structure (PDB 8H77) 44 led to the exit of TCDD through the gate, i.e. , in a fashion similar to the exit of JH III from the GCE cavity.…”

Section: Resultsmentioning

confidence: 99%

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Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

Sedlak,

Tuma,

Kolla

et al. 2024

Preprint

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Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that synthetic insect juvenile hormone agonists might interfere with AHR signaling in human cells.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

Sedlak,

Tuma,

Kolla

et al. 2024

Preprint

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“…Similar to the affinity column experiments, the cell experiments confirmed that the AhR complex is AhR-HSP90-XAP2 when DHNA is the ligand. The structure of the AhR-molecular chaperone complex has recently been reported from two groups using cryo-electron microscopy [29,30]. In the Cryo-EM structure of the intact HSP90-AhR-p23-XAP2 complex, AhR is shaped like a ball with threads hanging down from the lumen of the HSP90 dimer and is considered a mature, stable, ligand-unbound structure [26].…”

Section: Discussionmentioning

confidence: 99%

“…Upon activation by ligand binding, the cytoplasmic AhR complex translocates to the nucleus. After nuclear translocation, p23 is separated, and the dissociated AhR from the HSP90‐AhR‐XAP2 complex forms an active heterodimer with ARNT and functions as a transcription factor [29].…”

Section: Discussionmentioning

confidence: 99%

The components of the AhR‐molecular chaperone complex differ depending on whether the ligands are toxic or non‐toxic

Narita,

Tamura,

Hatakeyama

et al. 2024

FEBS Letters

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The aryl hydrocarbon receptor (AhR) forms a complex with the HSP90‐XAP2‐p23 molecular chaperone when the cells are exposed to toxic compounds. Recently, 1,4‐dihydroxy‐2‐naphthoic acid (DHNA) was reported to be an AhR ligand. Here, we investigated the components of the molecular chaperone complex when DHNA binds to AhR. Proteins eluted from the 3‐Methylcolanthrene‐affinity column were AhR‐HSP90‐XAP2‐p23 complex. The AhR‐molecular chaperone complex did not contain p23 in the eluents from the DHNA‐affinity column. In 3‐MC‐treated cells, AhR formed a complex with HSP90‐XAP2‐p23 and nuclear translocation occurred within 30 min, while in DHNA‐treated cells, AhR formed a complex with AhR‐HSP90‐XAP2, and translocation was slow from 60 min. Thus, the AhR activation mechanism may differ when DHNA is the ligand compared to toxic ligands.

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“…The study elucidates AHR's promiscuity in binding ligands, particularly planar ones, and reveals flexibility in the ligand entry site. Residues forming π-interactions with the ligand are highlighted, and the large interior cavity of the ligandbinding pocket accommodates molecules of varying sizes, explaining receptor promiscuity (Figure 4I) [88].…”

Section: Hsp90:ahr:xap2 Unusual Cochaperone Complexmentioning

confidence: 99%

New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

Minari,

Balasco Serrão,

Borges

2024

BioChem

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Heat Shock Protein 90 (Hsp90) acts as a crucial molecular chaperone, playing an essential role in activating numerous signaling proteins. The intricate mechanism of Hsp90 involving ATPase-coupled conformational changes and interactions with cochaperone proteins has been elucidated through biochemical and structural analyses, revealing its activation mechanism and its diverse set of “client” proteins. Despite recent advancements, certain aspects of Hsp90’s ATPase-coupled mechanism remain contentious, and the specific nature of the alterations induced by Hsp90 in client proteins remains largely undiscovered. In this review, we explore the current understanding of Hsp90’s structure and function, drawing insights from single-particle cryoEM studies. Structural studies on Hsp90 using cryoEM have provided valuable insights into the structural dynamics and interactions of this molecular chaperone. CryoEM structures have been instrumental in understanding the ATPase-coupled conformational changes that Hsp90 undergoes during its chaperone cycle. We also highlight recent progress in elucidating the structure of the ATP-bound state of the complete dimeric chaperone. Furthermore, we delve into the roles played by the multitude of cochaperones that collaborate with Hsp90, providing a glimpse into their biochemical mechanisms through the newly obtained cryoEM structures of Hsp90 cochaperone complexes.

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Cryo-EM structure of the cytosolic AhR complex

Cited by 19 publications

References 57 publications

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

The components of the AhR‐molecular chaperone complex differ depending on whether the ligands are toxic or non‐toxic

New Insights into Hsp90 Structural Plasticity Revealed by cryoEM

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