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

Area of Science:

• Endocrinology
• Molecular Biology
• Toxicology

Background:

• The bHLH-PAS family includes key receptors like the aryl hydrocarbon receptor (AHR) in vertebrates and the juvenile hormone receptor (JHR) in insects.
• Both AHR and JHR bind small molecules to regulate physiological processes, with JHR targeted by insecticides and AHR involved in human endocrine homeostasis and response to pollutants.

Purpose of the Study:

• To investigate whether compounds activating insect JHR signaling can also affect human AHR signaling.
• To identify novel JHR agonists and explore the structural basis for ligand binding and receptor activation in both JHR and AHR.

Main Methods:

• Screening of a 50,000-compound library using a Drosophila cell-based reporter system to identify JHR agonists.
• Testing identified JHR agonists in a human cell line reporter assay to assess AHR signaling modulation.
• Utilizing molecular dynamics modeling and site-directed mutagenesis to compare ligand-binding cavities and interactions for AHR and JHR.

Main Results:

• Identification of 93 novel JHR agonists, with 26% also modulating human AHR signaling, indicating significant overlap in their agonist repertoires.
• Molecular modeling revealed both ligand-specific and conserved features in the binding cavities of AHR and JHR.
• Mutagenesis studies confirmed the significance of predicted ligand-receptor interactions.

Conclusions:

• Synthetic juvenile hormone agonists targeting insect JHR may act as endocrine disruptors for the human AHR pathway.
• Structural similarities and differences in ligand-binding pockets explain the cross-reactivity between JHR and AHR agonists.
• Findings highlight potential risks of insecticide exposure to human endocrine health.