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Modeling the binding of diverse ligands within the Ah receptor ligand binding domain

Scientific Reports. 2019;9(1):1-14 DOI 10.1038/s41598-019-47138-z


Journal Homepage

Journal Title: Scientific Reports

ISSN: 2045-2322 (Online)

Publisher: Nature Publishing Group

LCC Subject Category: Medicine | Science

Country of publisher: United Kingdom

Language of fulltext: English

Full-text formats available: PDF, HTML



Sara Giani Tagliabue (Department of Earth and Environmental Sciences, University of Milano-Bicocca)

Samantha C. Faber (Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill)

Stefano Motta (Department of Earth and Environmental Sciences, University of Milano-Bicocca)

Michael S. Denison (Department of Environmental Toxicology, University of California)

Laura Bonati (Department of Earth and Environmental Sciences, University of Milano-Bicocca)


Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 20 weeks


Abstract | Full Text

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.