A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience |
Volume | 28 |
Issue number | 43 |
Pages (from-to) | 10937-42 |
Number of pages | 6 |
ISSN | 0270-6474 |
DOIs | |
Publication status | Published - 22 Oct 2008 |
- Amino Acids, Aromatic, Animals, Binding Sites, Cations, Glycine, Humans, Microinjections, Models, Molecular, Mutagenesis, Site-Directed, Oocytes, Phenylalanine, Protein Binding, Protein Conformation, Protein Structure, Secondary, Radioligand Assay, Receptors, Glycine, Structure-Activity Relationship, Xenopus laevis
Research areas
ID: 122597853