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

Authors :
Michael S. Denison
Anatoly A. Soshilov
Source :
Soshilov, AA; & Denison, MS. (2014). Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Molecular and Cellular Biology, 34(9), 1707-1719. doi: 10.1128/MCB.01183-13. UC Office of the President: Research Grants Program Office (RGPO). Retrieved from: http://www.escholarship.org/uc/item/3968795z, Molecular and cellular biology, vol 34, iss 9
Publication Year :
2014
Publisher :
Informa UK Limited, 2014.

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by structurally diverse chemicals. To examine the mechanisms responsible for the promiscuity in AhR ligand binding, we determined the effects of mutations within the AhR ligand-binding domain (LBD) on the activity of diverse AhR ligands. Site-directed mutagenesis identified Ile319 of the mouse AhR and, to a lesser extent, Phe318 as residues involved in ligand-selective modulation of AhR transformation using a panel of 12 AhR ligands. These ligands could be categorized into four distinct structurally related groups based on their ability to activate AhR mutants at position 319 in vitro. The mutation I319K was selectively activated by FICZ and not by other examined ligands in vitro and in cell culture. F318L and F318A mutations resulted in the conversion of AhR agonists β-naphthoflavone and 3-methylcholanthrene, respectively, into partial agonists/ antagonists. Hsp90 binding to the AhR was decreased with several mutations and was inversely correlated with AhR ligand-binding promiscuity. Together, these data define overlapping amino acid residues within the AhR LBD involved in the selectivity of ligand binding, the agonist or antagonist mode of ligand binding, and hsp90 binding and provide insights into the ligand diversity of AhR activators. © 2014, American Society for Microbiology.

Details

ISSN :
10985549
Volume :
34
Database :
OpenAIRE
Journal :
Molecular and Cellular Biology
Accession number :
edsair.doi.dedup.....691777d094d9b0b5c0542145e3973ce5
Full Text :
https://doi.org/10.1128/mcb.01183-13