Different Structural Requirements of the Ligand Binding Domain of the Aryl Hydrocarbon Receptor for High- and Low-Affinity Ligand Binding and Receptor Activation

2004 ◽  
Vol 65 (2) ◽  
pp. 416-425 ◽  
Author(s):  
Maria Backlund ◽  
Magnus Ingelman-Sundberg
Keyword(s):  
Ligand Binding ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Structural Requirements ◽  
Aryl Hydrocarbon ◽  
Affinity Ligand

scholarly journals Modeling of the Aryl Hydrocarbon Receptor (AhR) Ligand Binding Domain and Its Utility in Virtual Ligand Screening to Predict New AhR Ligands

2009 ◽  
Vol 52 (18) ◽  
pp. 5635-5641 ◽  
Author(s):  
William H. Bisson ◽  
Daniel C. Koch ◽  
Edmond F. O’Donnell ◽  
Sammy M. Khalil ◽  
Nancy I. Kerkvliet ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Aryl Hydrocarbon Receptor ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Aryl Hydrocarbon ◽  
Ligand Screening ◽  
Virtual Ligand Screening

scholarly journals An Aryl Hydrocarbon Receptor from the Caecilian Gymnopis multiplicata Suggests Low Dioxin Affinity in the Ancestor of All Three Amphibian Orders

2019 ◽  
Author(s):  
Sarah A. Kazzaz ◽  
Sara Giani Tagliabue ◽  
Diana G. Franks ◽  
Michael S. Denison ◽  
Mark E. Hahn ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Aryl Hydrocarbon Receptor ◽  
Common Ancestor ◽  
Homology Model ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Ambystoma Mexicanum ◽  
List Type ◽  
Aryl Hydrocarbon ◽  
And Function

AbstractThe aryl hydrocarbon receptor (AHR) plays pleiotropic roles in the development and physiology of vertebrates in conjunction with xenobiotic and endogenous ligands. It is best known for mediating the toxic effects of dioxin-like pollutants such as 2,3,7,8-tetracholordibenzo-p-dioxin (TCDD). While most vertebrates possess at least one AHR that binds TCDD tightly, amphibian AHRs bind TCDD with very low affinity. Previous analyses of AHRs from Xenopus laevis (a frog; order Anura) and Ambystoma mexicanum (a salamander; order Urodela) identified three amino acid residues in the ligand-binding domain (LBD) that underlie low-affinity binding. In X. laevis AHR1β, these are A354, A370, and N325. Here we extend the analysis of amphibian AHRs to the caecilian Gymnopis multiplicata, representing the remaining extant amphibian order, Apoda. G. multiplicata AHR groups with the monophyletic vertebrate AHR/AHR1 clade. The LBD includes all three signature residues of low TCDD affinity, and a structural homology model suggests that its architecture closely resembles those of other amphibians. In transactivation assays, the EC50 for reporter gene induction by TCDD was 17.17 nM, comparable to X. laevis AhR1β (26.23 nM) and Ambystoma AHR (34.09 nM) and dramatically higher than mouse AhR (0.13 nM), a trend generally reflected in direct measures of TCDD binding. These shared properties distinguish amphibian AHRs from the high-affinity proteins typical of both more ancient vertebrate groups (teleost fish) and those that appeared more recently (tetrapods). We suggest that AHRs with low TCDD affinity represent a basal characteristic that evolved in a common ancestor of all three extant amphibian groups.Research HighlightsA caecilian aryl hydrocarbon receptor exhibits low dioxin binding and sensitivity.The protein’s ligand-binding domain resembles frog and salamander AHRs in structure and function.AHR with low dioxin affinity likely evolved in a common ancestor of all three extant amphibian groups.Graphical Abstract

Structure of the activation domain of the GM-CSF/IL-3/IL-5 receptor common β-chain bound to an antagonist

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2491-2498 ◽  
Author(s):  
Jamie Rossjohn ◽  
William J. McKinstry ◽  
Joanna M. Woodcock ◽  
Barbara J. McClure ◽  
Timothy R. Hercus ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Site ◽  
Interleukin 2 ◽  
Receptor Activation ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Fab Fragment ◽  
Gm Csf ◽  
Single Receptor ◽  
Β Chain

Abstract Heterodimeric cytokine receptors generally consist of a major cytokine-binding subunit and a signaling subunit. The latter can transduce signals by more than 1 cytokine, as exemplified by the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and IL-6 receptor systems. However, often the signaling subunits in isolation are unable to bind cytokines, a fact that has made it more difficult to obtain structural definition of their ligand-binding sites. This report details the crystal structure of the ligand-binding domain of the GM-CSF/IL-3/IL-5 receptor β-chain (βc) signaling subunit in complex with the Fab fragment of the antagonistic monoclonal antibody, BION-1. This is the first single antagonist of all 3 known eosinophil-producing cytokines, and it is therefore capable of regulating eosinophil-related diseases such as asthma. The structure reveals a fibronectin type III domain, and the antagonist-binding site involves major contributions from the loop between the B and C strands and overlaps the cytokine-binding site. Furthermore, tyrosine421 (Tyr421), a key residue involved in receptor activation, lies in the neighboring loop between the F and G strands, although it is not immediately adjacent to the cytokine-binding residues in the B-C loop. Interestingly, functional experiments using receptors mutated across these loops demonstrate that they are cooperatively involved in full receptor activation. The experiments, however, reveal subtle differences between the B-C loop and Tyr421, which is suggestive of distinct functional roles. The elucidation of the structure of the ligand-binding domain of βc also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous receptor systems.

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