Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex

Area of Science:

• Molecular biology
• Structural biology
• Biochemistry

Background:

• The aryl hydrocarbon receptor (AHR) is a transcription factor sensing various small molecules.
• AHR activation involves translocation to the nucleus, forming a complex with ARNT to regulate gene expression, including detoxification and immune responses.

Purpose of the Study:

• To elucidate the molecular mechanisms of AHR's high-affinity binding and activation by diverse ligands.
• To provide structural insights into the AHR-ARNT-DNA complex formation and ligand-driven activation.

Main Methods:

• X-ray crystallography of AHR-ARNT-DNA complexes bound to six different AHR ligands.
• Analysis of protein-ligand interactions and structural rearrangements.

Main Results:

• Revealed an unconventional subunit assembly between AHR and ARNT PAS-B domains.
• Identified eight conserved residues in AHR's PAS-B domain mediating ligand binding via hydrophobic and π-π interactions.
• Uncovered a ligand-driven activation mechanism involving a structural transition for ARNT heterodimer stabilization and transcriptionally competent assembly.

Conclusions:

• The study provides key structural information on AHR ligand binding and activation mechanisms.
• Findings are crucial for the future development of novel AHR-targeting therapeutics.