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XB-ART-38813
J Neurosci October 22, 2008; 28 (43): 10937-42.
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A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue.

Pless SA , Millen KS , Hanek AP , Lynch JW , Lester HA , Lummis SC , Dougherty DA .


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.

PubMed ID: 18945901
PMC ID: PMC2649377
Article link: J Neurosci
Grant support: [+]

Species referenced: Xenopus laevis

References [+] :
Beene, Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine. 2002, Pubmed, Xenbase