RT Journal Article
SR Electronic
T1 A CATION-Π INTERACTION AT A PHENYLALANINE RESIDUE IN THE GLYCINE RECEPTOR BINDING SITE IS CONSERVED FOR DIFFERENT AGONISTS
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.069583
DO 10.1124/mol.110.069583
A1 Stephan Pless
A1 Ariel Hanek
A1 Kerry Price
A1 Joseph W. Lynch
A1 Henry A. Lester
A1 Dennis Dougherty
A1 Sarah C R Lummis
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/01/25/mol.110.069583.abstract
AB 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.