<scp>A</scp>h‐Receptor (Dioxin Receptor)

Bittinger, Mark; Bradfield, Christopher A.

doi:10.1002/0471203076.emm1158

Cited by 1 publication

(1 citation statement)

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“…It is also possible that the less restrictive gpAhR binding pocket accomodates a different set of endogenous ligands, and/or that metabolic pathways producing endogenous ligands (e.g. from tryptophan [34]) may differ quantitatively or qualitatively between guinea pig and other species. Clearly, further work is necessary to identify endogenous ligands and answer interesting questions regarding how they differ from toxic xenobiotic ligands in their regulation of AhR signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor

Henry

Gasiewicz

2008

Archives of Biochemistry and Biophysics

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The aryl hydrocarbon receptor (AhR) mediates the toxicity of dioxins and related xenobiotics. Other chemicals also bind the AhR to elicit either agonist or antagonist responses. Here we used sitedirected mutagenesis within the ligand binding domain of murine AhR to probe for specific residues that might interact differentially with the antagonist 3'-methoxy-4'-nitroflavone (MNF) compared with the prototypical agonist TCDD. Reduced 3 H-TCDD binding, dioxin-response element (DRE) binding, and transcriptional activity were observed for several point mutants. One mutation, R355I, changed the response to MNF from antagonist to agonist. Notably, Ile is the residue found in the guinea pig AhR, towards which MNF has partial agonist activity in contrast to its strong antagonist activity in mouse. A similar reversal of response to MNF was observed in chimeric AhRs in which the C-terminal region of mAhR was replaced with the guinea pig C-terminal region. These data demonstrate that different amino acids can be important in binding of different AhR ligands and can mediate distinct responses. The ultimate response of the AhR also depends on how other portions of the receptor protein are functionally coupled to the initial ligand binding event.

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Section: Discussionmentioning

confidence: 99%