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Cited by 10Effects and risks of endocrine disrupting chemicalsToxic Organic Pollutants ImpactReceptor Mechanisms and Signaling

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

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Sedlak, David, Tuma, Roman, Kolla, Jayaprakash Narayana, Mokhamatam, Raveendra Babu, Bahrova, Liliia, Lisova, Michaela, Bittova, Lenka, Jindra, Marek·2025·Journal of Molecular Biology
DOI 10.1016/j.jmb.2024.168883

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Abstract

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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Metadata

Authors
Sedlak, D., Tuma, R., Kolla, J. N., Mokhamatam, R. B., Bahrova, L., Lisova, M., Bittova, L., & Jindra, M.
Affiliations
Czech Academy of Sciences (CZ)
Corresponding author
Jindra, Marek
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2025-01
Volume
437
Issue
2
Pages
168883
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2024.168883
OpenAlex
W4404733720
Cited by
10
References
7
Citations by year
2026: 4 · 2025: 5
FWCI
1.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministerstvo Školství, Mládeže a Tělovýchovy (68378050‐KAV‐NPUI, CZ.02.1.01/0.0/0.0/15_003/0000441, 68378050, CZ.02.1.01/0.0/0.0/15_003, CZ.02.1.01, LM2018130)
  • Grantová Agentura České Republiky (CZ.02.1.01/0.0, CZ.02.1.01, CZ.02.1.01/0.0/0.0/15_003/0000441, 68378050, GX20-05151X)
  • Akademie Věd České Republiky (68378050‐KAV‐NPUI, 68378050)
  • European Regional Development Fund (02.1.01/0.0/0.0, CZ.02.1.01/0.0/0.0/15 003/0000441, CZ.02, CZ.02.1.01, CZ.02.1.01/0.0/0.0)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
juvenile hormone receptor, aryl hydrocarbon receptor, bHLH-PAS transcription factors, endocrine disruptors, ligand-binding cavity, Drosophila melanogaster
MeSH terms
Animals, Cell Line, Drosophila melanogaster, Humans, Juvenile Hormones, Ligands, Protein Binding, Transcription Factors, Signal Transduction, Receptors, Aryl Hydrocarbon, Drosophila Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Small Molecule Libraries

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