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

Pless, Stephan A. and Millen, Kat S. and Hanek, Ariele P. and Lynch, Joseph W. and Lester, Henry A. and 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). pp. 10937-10942. ISSN 0270-6474. PMCID PMC2649377. https://resolver.caltech.edu/CaltechAUTHORS:PLEjns08

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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 GABAA 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.2540-08.2008DOIArticle
http://www.jneurosci.org/cgi/content/short/28/43/10937PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649377/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Lummis, Sarah C. R.0000-0001-9410-9805
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2008 Society for Neuroscience. Received August 6, 2008; accepted August 9, 2008. This work was supported by the Wellcome Trust (S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science), a Biotechnology and Biological Sciences Research Council studentship (K.S.M.), National Institutes of Health Grants NS11756 and NS34407, the Australian Research Council, a National Health and Medical Research Council of Australia Senior Research Fellowship (J.W.L.), and a University of Queensland International Postgraduate Research Scholarship (S.A.P.). S.C.R.L. and D.A.D. contributed equally to this work.
Funders:
Funding AgencyGrant Number
Wellcome TrustUNSPECIFIED
Biotechnology and Biological Sciences Research Council (BBSRC)UNSPECIFIED
NIHNS11756
NIHNS34407
Australian Research CouncilUNSPECIFIED
National Health and Medical Research Council (NHMRC)UNSPECIFIED
University of QueenslandUNSPECIFIED
Subject Keywords:ligand-gated ion channel; Cys-loop receptor; cation-{pi} interaction; unnatural amino acids; nonsense suppression; neurotransmitter
Issue or Number:43
PubMed Central ID:PMC2649377
Record Number:CaltechAUTHORS:PLEjns08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:PLEjns08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12182
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:28 Oct 2008 17:37
Last Modified:09 Mar 2020 13:19

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