Abstract
The Ah receptor (AhR) is a ligand-dependent transcription factor belonging to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) superfamily. Binding to and activation of the AhR by a variety of chemicals results in the induction of expression of diverse genes and production of a broad spectrum of biological and toxic effects. The AhR also plays important roles in several physiological responses, which has led it to become a novel target for the development of therapeutic drugs. Differences in the interactions of various ligands within the AhR ligand binding domain (LBD) may contribute to differential modulation of AhR functionality. We combined computational and experimental analyses to investigate the binding modes of a group of chemicals representative of major classes of AhR ligands. On the basis of a novel computational approach for molecular docking to the homology model of the AhR LBD that includes the receptor flexibility, we predicted specific residues within the AhR binding cavity that play a critical role in binding of three distinct groups of chemicals. The prediction was validated by site-directed mutagenesis and evaluation of the relative ligand binding affinities for the mutant AhRs. These results provide an avenue for understanding ligand modulation of the AhR functionality and for rational drug design.
Highlights
The Ah receptor (AhR) is a ligand-activated transcription factor belonging to the basic helix-loop-helix Per-Arnt-Sim superfamily of regulatory proteins[1,2]
To increase our understanding of the molecular determinants of differential ligand binding to the AhR, a set of 10 representative ligands belonging to different chemical classes were selected for detailed analysis (Fig. 1a)
While TCDD and TCDF show elongated and planar structures, the shorter PCB126 molecule is characterized by rotation of the chlorinated rings around the central bond, that leads to a higher three-dimensional hindrance
Summary
The Ah receptor (AhR) is a ligand-activated transcription factor belonging to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) superfamily of regulatory proteins[1,2]. The binding of the ligand:AhR:ARNT complex to its specific DNA recognition site, the dioxin responsive element (DRE), leads to transcription of the target genes In addition to this mechanism, several non-canonical pathways related to AhR function have been described[9,10]. It has been suggested that these differences may contribute to ligand-specific modulation of the AhR functionality or to alterations of the AhR signaling pathway as a result of ligand-dependent changes in the AhR conformation, or in the structure of either the AhR:ARNT dimer or other AhR:protein complexes[18] This may lead the activated receptor to interact with different protein partners and/or coactivators, to bind to unconventional DNA sequences, and to differentially alter gene expression[5,10,18]
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