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Published October 22, 2008 | Published
Journal Article Open

A Cation-π Interaction in the Binding Site of the Glycine Receptor Is Mediated by a Phenylalanine Residue

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 GABAA 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 EC50 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.

Additional Information

© 2008 Society for Neuroscience. Received August 6, 2008; accepted August 9, 2008. This work was supported by the Wellcome Trust (S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science), a Biotechnology and Biological Sciences Research Council studentship (K.S.M.), National Institutes of Health Grants NS11756 and NS34407, the Australian Research Council, a National Health and Medical Research Council of Australia Senior Research Fellowship (J.W.L.), and a University of Queensland International Postgraduate Research Scholarship (S.A.P.). S.C.R.L. and D.A.D. contributed equally to this work.

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August 22, 2023
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