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Open AccessArticle

A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain

1
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
2
Cancer Research Laboratory, Corvallis, OR 97331, USA
3
Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
4
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biology 2014, 3(4), 645-669; https://doi.org/10.3390/biology3040645
Received: 23 May 2014 / Revised: 24 September 2014 / Accepted: 24 September 2014 / Published: 17 October 2014
(This article belongs to the Special Issue Screening for Biologically Active Compounds)
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand. View Full-Text
Keywords: aryl hydrocarbon receptor; ligand binding domain; agonist; antagonist; ligand-guided optimization; virtual ligand screening; molecular dynamics; HSP90 aryl hydrocarbon receptor; ligand binding domain; agonist; antagonist; ligand-guided optimization; virtual ligand screening; molecular dynamics; HSP90
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Perkins, A.; Phillips, J.L.; Kerkvliet, N.I.; Tanguay, R.L.; Perdew, G.H.; Kolluri, S.K.; Bisson, W.H. A Structural Switch between Agonist and Antagonist Bound Conformations for a Ligand-Optimized Model of the Human Aryl Hydrocarbon Receptor Ligand Binding Domain. Biology 2014, 3, 645-669.

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