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The Journal of Neuroscience, October 22, 2008, 28(43):10937-10942; doi:10.1523/JNEUROSCI.2540-08.2008

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

Stephan A. Pless,¹ Kat S. Millen,² Ariele P. Hanek,⁴ Joseph W. Lynch,¹ Henry A. Lester,⁵ Sarah C. R. Lummis,^2,3 * and Dennis A. Dougherty^4 *

¹School of Biomedical Sciences and Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia, ²Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom, ³Division of Neurobiology, Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom, and Divisions of ⁴Chemistry and Chemical Engineering and ⁵Biology, California Institute of Technology, Pasadena, California 91125

Correspondence should be addressed to Sarah C. R. Lummis, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.

Cys-loop receptor binding sites characteristically contain many aromatic amino acids. In nicotinic ACh and 5-HT₃ receptors, a Trp residue forms a cation- 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- 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- binding ability of the fluorinated Phe derivatives at position 159, but not at positions 207 or 63, indicating a single cation- 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- interaction between Phe and a neurotransmitter.

Key words: ligand-gated ion channel; Cys-loop receptor; cation- interaction; unnatural amino acids; nonsense suppression; neurotransmitter

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Received Aug. 6, 2008; accepted Aug. 9, 2008.

Correspondence should be addressed to Sarah C. R. Lummis, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.

This article has been cited by other articles:

				S. A. Pless and J. W. Lynch Magnitude of a Conformational Change in the Glycine Receptor {beta}1-{beta}2 Loop Is Correlated with Agonist Efficacy J. Biol. Chem., October 2, 2009; 284(40): 27370 - 27376. [Abstract] [Full Text] [PDF]

				S. A. Pless and J. W. Lynch Ligand-specific Conformational Changes in the {alpha}1 Glycine Receptor Ligand-binding Domain J. Biol. Chem., June 5, 2009; 284(23): 15847 - 15856. [Abstract] [Full Text] [PDF]

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