title: In silico analysis of the interaction of avian aryl hydrocarbon receptors and dioxins to decipher isoform-, ligand-, and species-specific activations.
abstract: The aryl hydrocarbon receptor (AHR) mediates toxic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds (DLCs). Avian species possess multiple AHR isoforms (AHR1, AHR1β, and AHR2) that exhibit species- and isoform-specific responses to ligands. To account for the ligand preference in terms of the structural features of avian AHRs, we generated in silico homology models of the ligand-binding domain of avian AHRs based on holo human HIF-2α (PDB entry 3H7W ). Molecular docking simulations of TCDD and other DLCs with avian AHR1s and AHR2s using ASEDock indicated that the interaction energy increased with the number of substituted chlorine atoms in congeners, supporting AHR transactivation potencies and World Health Organization TCDD toxic equivalency factors of congeners. The potential interaction energies of an endogenous AHR ligand, 6-formylindolo [3,2-b] carbazole (FICZ) to avian AHRs were lower than those of TCDD, which was supported by a greater potency of FICZ for in vitro AHR-mediated transactivation than TCDD. The molecular dynamics simulation revealed that mean square displacements in Ile324 and Ser380 of TCDD-bound AHR1 of the chicken, the most sensitive species to TCDD, were smaller than those in other avian AHR1s, suggesting that the dynamic stability of these amino acid residues contribute to TCDD preference. For avian AHR2, the corresponding residues (Val/Ser or Val/Ala type) were not responsible for differential TCDD sensitivity. Application of the three-dimensional reference interaction site model showed that the stabilization of TCDD binding to avian AHRs may be due to the solvation effect depending on the characteristics of two amino acids corresponding to Ile324 and Ser380 in chicken AHR1. This study demonstrates that in silico simulations of AHRs and ligands could be used to predict isoform-, ligand-, and species-specific interactions.
authors.affiliation: †Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama 790-8577, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Hirano
authors.affiliation: ‡Department of Life and Nanopharmaceutical Science and Department of Biology, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Hwang
authors.affiliation: ‡Department of Life and Nanopharmaceutical Science and Department of Biology, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Korea.
authors.forename: Hae-Jeong
authors.initials: HJ
authors.lastname: Park
authors.affiliation: ‡Department of Life and Nanopharmaceutical Science and Department of Biology, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Korea.
authors.forename: Su-Min
authors.initials: SM
authors.lastname: Bak
authors.affiliation: †Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama 790-8577, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Iwata
authors.affiliation: ‡Department of Life and Nanopharmaceutical Science and Department of Biology, Kyung Hee University, Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001665:Binding Sites; D001717:Birds / Q000378:metabolism*; D002227:Carbazoles / Q000737:chemistry / Q000378:metabolism; D002645:Chickens / Q000378:metabolism; D003198:Computer Simulation; D004147:Dioxins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry; D013045:Species Specificity; D040681:Structural Homology, Protein
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D002227:Carbazoles; D004147:Dioxins; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D020033:Protein Isoforms; D018336:Receptors, Aryl Hydrocarbon; D012997:Solvents