Exploration of Agonist and Antagonist Binding Sites within the Cytosolic AHR Complex Using Molecular Modeling

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in metabolism, cell motility, development, and immune responses. Its dysregulation is linked to various diseases, including cancer, in which it can enhance tumor progression and suppress immune responses. High-resolution cryo-electron microscopy (cryo-EM) structures of the human cytosolic AHR complex have recently been solved and have provided insights into its agonist-binding mechanisms. However, our understanding of AHR antagonist binding remains limited. Our computational study, using the structure of the indirubin-bound human cytosolic AHR complex together with state-of-the-art docking algorithms and molecular dynamics simulations, suggests that AHR antagonists may bind either to the ligand-binding pocket or to alternative, as yet unexplored, sites outside of the ligand-binding pocket. These findings suggest novel molecular mechanisms of AHR inhibition and provide the foundation for experimental evaluation to advance our understanding of the therapeutic potential of current AHR inhibitors and to support future drug development efforts.