Referenced in: none

Automatically associated channels: Kir2.3

Title: A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue.

Authors: Stephan A Pless, Kat S Millen, Ariele P Hanek, Joseph W Lynch, Henry A Lester, Sarah C R Lummis, Dennis A Dougherty

Journal, date & volume: J. Neurosci., 2008 Oct 22 , 28, 10937-42

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18945901

Abstract
Cys-loop receptor binding sites characteristically contain many aromatic amino acids. In nicotinic ACh and 5-HT3 receptors, a Trp residue forms a cation-pi interaction with the agonist, whereas in GABA(A) receptors, a Tyr performs this role. The glycine receptor binding site, however, contains predominantly Phe residues. Homology models suggest that two of these Phe side chains, Phe159 and Phe207, and possibly a third, Phe63, are positioned such that they could contribute to a cation-pi interaction with the primary amine of glycine. Here, we test this hypothesis by incorporation of a series of fluorinated Phe derivatives using unnatural amino acid mutagenesis. The data reveal a clear correlation between the glycine EC(50) value and the cation-pi binding ability of the fluorinated Phe derivatives at position 159, but not at positions 207 or 63, indicating a single cation-pi interaction between glycine and Phe159. The data thus provide an anchor point for locating glycine in its binding site, and demonstrate for the first time a cation-pi interaction between Phe and a neurotransmitter.