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A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists

Pless, Stephan A. and Hanek, Ariele P. and Price, Kerry L. and Lynch, Joseph W. and Lester, Henry A. and Dougherty, Dennis A. and Lummis, Sarah C. R. (2011) A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists. Molecular Pharmacology, 79 (4). pp. 742-748. ISSN 0026-895X. PMCID PMC3063724. doi:10.1124/mol.110.069583.

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Cation-π interactions have been demonstrated to play a major role in agonist-binding in Cys-loop receptors. However, neither the aromatic amino acid contributing to this interaction nor its location is conserved among Cys-loop receptors. Likewise, it is not clear how many different agonists of a given receptor form a cation-π interaction or, if they do, whether it is with the same aromatic amino acid as the major physiological agonist. We demonstrated previously that Phe159 in the glycine receptor (GlyR) α1 subunit forms a strong cation-π interaction with the principal agonist, glycine. In the current study, we investigated whether the lower efficacy agonists of the human GlyR β-alanine and taurine also form cation-π interactions with Phe159. By incorporating a series of unnatural amino acids, we found cation-π interactions between Phe159 and the amino groups of β-alanine and taurine. The strengths of these interactions were significantly weaker than for glycine. Modeling studies suggest that β-alanine and taurine are orientated subtly differently in the binding pocket, with their amino groups further from Phe159 than that of glycine. These data therefore show that similar agonists can have similar but not identical orientations and interactions in the binding pocket and provide a possible explanation for the lower potencies of β-alanine and taurine.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Lummis, Sarah C. R.0000-0001-9410-9805
Additional Information:© 2011 The American Society for Pharmacology and Experimental Therapeutics. Received October 22, 2010; accepted January 4, 2011. Published online before print January 25, 2011. This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS11756, NS34407]; the Wellcome Trust [Grant RG81925]; a Wellcome Trust Senior Research Fellowship in Basic Biomedical Science (to S.C.R.L.); the European Union (Grant FP7NeuroCypres); the Australian Research Council; and the National Health and Medical Research Council of Australia. Authorship Contributions: Participated in research design: Pless, Lynch, Lester, Dougherty, and Lummis. Conducted experiments: Pless, Hanek, Price, and Lummis. Contributed new reagents or analytic tools: Dougherty. Performed data analysis: Pless, Hanek, Price, and Lummis. Wrote or contributed to the writing of the manuscript: Pless, Hanek, Price, Lynch, Lester, Dougherty, and Lummis. Other: Lynch, Lester, Dougherty, and Lummis acquired funding.
Funding AgencyGrant Number
Wellcome TrustRG81925
European UnionFP7 NeuroCypres
Australian Research CouncilUNSPECIFIED
National Health and Medical Research Council (Australia)UNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC3063724
Record Number:CaltechAUTHORS:20110404-100247422
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Official Citation: Stephan A. Pless, Ariele P. Hanek, Kerry L. Price, Joseph W. Lynch, Henry A. Lester, Dennis A. Dougherty, and Sarah C. R. Lummis A Cation-π Interaction at a Phenylalanine Residue in the Glycine Receptor Binding Site Is Conserved for Different Agonists Mol Pharmacol April 2011 79:742-748; published ahead of print January 25, 2011, doi:10.1124/mol.110.069583
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:23223
Deposited By: Ruth Sustaita
Deposited On:12 Apr 2011 15:21
Last Modified:09 Nov 2021 16:12

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