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

## TL;DR

This paper explores how agonists and antagonists bind to the AHR complex using molecular modeling to uncover new inhibition mechanisms.

## Contribution

The study identifies potential antagonist binding sites outside the known ligand-binding pocket in the AHR complex.

## Key findings

- AHR antagonists may bind to the ligand-binding pocket or alternative sites.
- Molecular modeling suggests novel mechanisms for AHR inhibition.
- Findings provide a foundation for developing new AHR inhibitors.

## Abstract

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.