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J Neurosci. 2008 Oct 22;28(43):10937-42. doi: 10.1523/JNEUROSCI.2540-08.2008.

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

Author information

1
School of Biomedical Sciences and Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.

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.

PMID:
18945901
PMCID:
PMC2649377
DOI:
10.1523/JNEUROSCI.2540-08.2008
[Indexed for MEDLINE]
Free PMC Article

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