Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
39608634
DOI
10.1016/j.jmb.2024.168883
PII: S0022-2836(24)00513-8
Knihovny.cz E-resources
- Keywords
- aryl hydrocarbon receptor, endocrine disruptors, high-throughput screening, juvenile hormone receptor, ligand binding domain,
- MeSH
- Cell Line MeSH
- Drosophila melanogaster metabolism MeSH
- Juvenile Hormones MeSH
- Small Molecule Libraries pharmacology MeSH
- Humans MeSH
- Ligands MeSH
- Drosophila Proteins * agonists metabolism chemistry genetics MeSH
- Receptors, Aryl Hydrocarbon * agonists metabolism chemistry genetics MeSH
- Signal Transduction drug effects MeSH
- Basic Helix-Loop-Helix Transcription Factors * agonists metabolism chemistry genetics MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- AHR protein, human MeSH Browser
- Juvenile Hormones MeSH
- Small Molecule Libraries MeSH
- Ligands MeSH
- Drosophila Proteins * MeSH
- Receptors, Aryl Hydrocarbon * MeSH
- Basic Helix-Loop-Helix Transcription Factors * MeSH
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.
CZ OPENSCREEN Institute of Molecular Genetics Czech Academy of Sciences Prague 14220 Czech Republic
Faculty of Science University of South Bohemia Ceske Budejovice 37005 Czech Republic
Institute of Molecular Genetics Czech Academy of Sciences Prague 14220 Czech Republic
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