A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists
| Autor: | Henry A. Lester, Ariele P. Hanek, Joseph W. Lynch, Dennis A. Dougherty, Kerry L. Price, Sarah C. R. Lummis, Stephan A. Pless |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Agonist
Taurine medicine.drug_class Stereochemistry Phenylalanine Glycine Receptor Binding beta-Alanine Biology 03 medical and health sciences chemistry.chemical_compound Xenopus laevis 0302 clinical medicine Receptors Glycine Cations Aromatic amino acids medicine Animals Humans Amino Acid Sequence Glycine receptor Conserved Sequence 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Binding Sites Dose-Response Relationship Drug Articles Amino acid chemistry Biochemistry Molecular Medicine Female 030217 neurology & neurosurgery |
| Popis: | Cation-π interactions have been demonstrated to play a major role in agonist-binding in Cys-loop receptors. However, neither the aromatic amino acid contributing to this interaction nor its location is conserved among Cys-loop receptors. Likewise, it is not clear how many different agonists of a given receptor form a cation-π interaction or, if they do, whether it is with the same aromatic amino acid as the major physiological agonist. We demonstrated previously that Phe159 in the glycine receptor (GlyR) α1 subunit forms a strong cation-π interaction with the principal agonist, glycine. In the current study, we investigated whether the lower efficacy agonists of the human GlyR β-alanine and taurine also form cation-π interactions with Phe159. By incorporating a series of unnatural amino acids, we found cation-π interactions between Phe159 and the amino groups of β-alanine and taurine. The strengths of these interactions were significantly weaker than for glycine. Modeling studies suggest that β-alanine and taurine are orientated subtly differently in the binding pocket, with their amino groups further from Phe159 than that of glycine. These data therefore show that similar agonists can have similar but not identical orientations and interactions in the binding pocket and provide a possible explanation for the lower potencies of β-alanine and taurine. |
| Databáze: | OpenAIRE |
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