Document Detail


Comparative analysis of homology models of the AH receptor ligand binding domain: verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor.
MedLine Citation:
PMID:  23286227     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness.
Authors:
Domenico Fraccalvieri; Anatoly A Soshilov; Sibel I Karchner; Diana G Franks; Alessandro Pandini; Laura Bonati; Mark E Hahn; Michael S Denison
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-14
Journal Detail:
Title:  Biochemistry     Volume:  52     ISSN:  1520-4995     ISO Abbreviation:  Biochemistry     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-29     Completed Date:  2013-03-25     Revised Date:  2014-01-30    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  714-25     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Amino Acid Sequence
Amino Acid Substitution*
Animals
Avian Proteins / chemistry*,  genetics,  physiology
Binding Sites
COS Cells
Cercopithecus aethiops
Environmental Pollutants / chemistry
Humans
Ligands
Models, Molecular
Molecular Sequence Data
Mutagenesis, Site-Directed
Protein Binding
Protein Structure, Tertiary
Receptors, Aryl Hydrocarbon / chemistry*,  genetics,  physiology
Structural Homology, Protein
Tetrachlorodibenzodioxin / chemistry
Transcriptional Activation
Zebrafish Proteins / chemistry*,  genetics,  physiology
Grant Support
ID/Acronym/Agency:
P42 ES004699/ES/NIEHS NIH HHS; P42 ES007381/ES/NIEHS NIH HHS; P42ES004699/ES/NIEHS NIH HHS; P42ES007381/ES/NIEHS NIH HHS; R01 ES006272/ES/NIEHS NIH HHS; R01 ES007685/ES/NIEHS NIH HHS; R01ES006272/ES/NIEHS NIH HHS; R01ES07685/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/AHR2 protein, zebrafish; 0/Ahr1b protein, zebrafish; 0/Avian Proteins; 0/Environmental Pollutants; 0/Ligands; 0/Receptors, Aryl Hydrocarbon; 0/Zebrafish Proteins; DO80M48B6O/Tetrachlorodibenzodioxin
Comments/Corrections

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