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

Pless, Stephan A., Millen, Kat S., Hanek, Ariele P., Lynch, Joseph W., Lester, Henry A., Lummis, Sarah C. R. and Dougherty, Dennis A. (2008) A Cation-π Interaction in the Binding Site of the Glycine Receptor Is Mediated by a Phenylalanine Residue. Journal of Neuroscience, 28 43: 10937-10942. doi:10.1523/JNEUROSCI.2540-08.2008


Author Pless, Stephan A.
Millen, Kat S.
Hanek, Ariele P.
Lynch, Joseph W.
Lester, Henry A.
Lummis, Sarah C. R.
Dougherty, Dennis A.
Title A Cation-π Interaction in the Binding Site of the Glycine Receptor Is Mediated by a Phenylalanine Residue
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
1529-2401
Publication date 2008-10-22
Year available 2008
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.2540-08.2008
Volume 28
Issue 43
Start page 10937
End page 10942
Total pages 6
Editor John H. R. Manusell
Place of publication Washington D.C., USA
Publisher Society for Neuroscience
Collection year 2009
Language eng
Subject C1
110903 Central Nervous System
920111 Nervous System and Disorders
Formatted 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 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.
Keyword ligand-gated ion channel
Cys-loop receptor
cation-{pi} interaction
unnatural amino acids
nonsense suppression
neurotransmitter
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
Queensland Brain Institute Publications
School of Biomedical Sciences Publications
 
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Created: Mon, 09 Mar 2009, 14:48:17 EST by Debra McMurtrie on behalf of Queensland Brain Institute