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Detection of the TCDD Binding-Fingerprint within the Ah Receptor Ligand Binding Domain by Structurally Driven Mutagenesis and Functional Analysis

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Division of Mathematical Biology, National Institute for Medical Research, The Ridgeway, London NW7 1AA, U.K.
§ Department of Environmental Toxicology, Meyer Hall, University of California, Davis, California 95616
Dipartimento di Scienze dell'Ambiente e del Territorio, Università degli Studi di Milano-Bicocca, Piazza della Scienza, 1, 20126 Milano, Italy
*To whom correspondence should be addressed. Phone: (530) 752-3879. Fax: (530) 752-3394. E-mail: [email protected]
Cite this: Biochemistry 2009, 48, 25, 5972–5983
Publication Date (Web):May 20, 2009
Copyright © 2009 American Chemical Society

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    The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix−loop−helix Per-Arnt-Sim (PAS)-containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Our previous three-dimensional homology model of the mouse AhR (mAhR) PAS B ligand binding domain allowed identification of the binding site and its experimental validation. We have extended this analysis by conducting comparative structural modeling studies of the ligand binding domains of six additional high-affinity mammalian AhRs. These results, coupled with site-directed mutagenesis and AhR functional analysis, have allowed detection of the “TCDD binding-fingerprint” of conserved residues within the ligand binding cavity necessary for high-affinity TCDD binding and TCDD-dependent AhR transformation DNA binding. The essential role of selected residues was further evaluated using molecular docking simulations of TCDD with both wild-type and mutant mAhRs. Taken together, our results dramatically improve our understanding of the molecular determinants of TCDD binding and provide a basis for future studies directed toward rationalizing the observed species differences in AhR sensitivity to TCDD and understanding the mechanistic basis for the dramatic diversity in AhR ligand structure.

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    Expression levels of in vitro synthesized wildtype and mutant AhRs. 35SLabeled wildtype (wt) and mutant AhRs (specific mutation indicated) were synthesized in vitro, denatured, and resolved by SDS−polyacrylamide gel electrophoresis and phosphoimager analysis of the dried gels as described in Materials and Methods (Figure 1). This material is available free of charge via the Internet at

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