AHR Ligands: Promiscuity in Binding and Diversity in Response

The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology

“…For a given cell type, they may even depend on the tissue milieu, such as an ongoing immune response (Sun et al, 2004;Frericks et al, 2007;Beischlag et al, 2008;Tappenden et al, 2013). There appears to be only one ligand binding pocket in the AhR [in the Per-ARNT-Sim-B domain], and the binding affinity of the best characterized highaffinity ligand, TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin), depends on only a few amino acids in the binding pocket of the AhR, as demonstrated by modeling and mutation studies (Whelan et al, 2010;DeGroot et al, 2012;Wu et al, 2013). The AhR can also be activated by numerous stress factors and substances that may not fit into the binding pocket, such as hyperoxia, oxidized low-density lipoproteins, hydrogen peroxide, ozone, or metals (references in Wincent et al, 2012).…”

Ligand Promiscuity of Aryl Hydrocarbon Receptor Agonists and Antagonists Revealed by Site-Directed Mutagenesis

“…he aryl hydrocarbon receptor (AhR) is a ligand-dependent nuclear receptor that mediates a broad spectrum of toxic and biological effects resulting from exposure to structurally diverse synthetic and natural compounds (1,2). The prototypical and most studied AhR ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant and known human carcinogen (3).…”

“…The prototypical and most studied AhR ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant and known human carcinogen (3). However, numerous other halogenated aromatic hydrocarbons (HAHs), polycyclic aromatic hydrocarbons (PAHs), and PAH-like compounds have also been described that possess high affinity for the AhR and can activate AhR-dependent signal transduction and produce diverse biological/toxic effects in various species (1,4). The AhR-mediated toxic and biological effects are produced by metabolically stable dioxin-like HAH ligands, including TCDD, 2,3,7,8-tetrachlorodibenzofuran (TCDF), 3,3=, 4,4=,5-pentachlorobiphenyl (PCB126), and others.…”

“…Ligandspecific modulation of the AhR signaling pathway has been suggested to result from ligand-dependent changes in the AhR which could allow it to interact with different nuclear factors or dimerization partners, to bind to unconventional DREs or unique DNA sequences, and/or to be bound by different coactivators (24)(25)(26)(27). For these changes to occur, significant differences in the binding interactions between ligands and amino acids within the AhR LBD must occur, and these differences must translate into alterations in AhR structure/function that ultimately lead to distinct ligand-and AhR-dependent biological responses (1,2).…”

“…The results of 3-dimensional protein structure analysis of PXR ligand binding has revealed that the dramatic structural promiscuity of PXR ligands can be explained by the characteristics of its binding pocket, which allows structurally diverse ligands to bind in a variety of different orientations and positions within the PXR LBD (28)(29)(30). By analogy, the structural diversity of AhR ligands may also result from differential interactions of ligands or classes of ligands with different residues within the AhR LBD (1,2). Consistent with this hypothesis is the identification of AhR antagonists that appear to be ligand selective in that they can preferentially inhibit the ability of some ligands (i.e., TCDD and related HAHs) to bind to and activate the AhR, while other AhR ligands (i.e., PAHs, flavonoids, indirubin) are not affected (31).…”