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

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 predo...

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Published in:The Journal of neuroscience 2008-10, Vol.28 (43), p.10937-10942
Main Authors: Pless, Stephan A, Millen, Kat S, Hanek, Ariele P, Lynch, Joseph W, Lester, Henry A, Lummis, Sarah C R, Dougherty, Dennis A
Format: Article
Language:English
Subjects:
Amino Acids, Aromatic - chemistry
Animals
Binding Sites - drug effects
Binding Sites - genetics
Binding Sites - physiology
Cations - chemistry
Glycine
Humans
Microinjections
Models, Molecular
Mutagenesis, Site-Directed - methods
Oocytes
Phenylalanine - metabolism
Protein Binding - genetics
Protein Binding - physiology
Protein Conformation
Protein Structure, Secondary
Radioligand Assay
Receptors, Glycine - genetics
Structure-Activity Relationship
Xenopus laevis
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Summary: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.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.2540-08.2008