Abstract
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 are conserved among Cys-loop receptors. Similarly, 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 previously demonstrated that Phe159 in the glycine receptor (GlyR) α1 subunit forms a strong cation-π interaction with the principal agonist, glycine. In this 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. Modelling 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.
- Glycine
- Structure-activity relationships and modeling
- Func. analysis receptor/ion channel mutants
- Mutagenesis/Chimeric approaches
- Received October 22, 2010.
- Revision received January 4, 2011.
- Accepted January 4, 2011.
- The American Society for Pharmacology and Experimental Therapeutics