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Molecular Pharmacology

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Research ArticleArticle

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

Stephan A. Pless, Ariele P. Hanek, Kerry L. Price, Joseph W. Lynch, Henry A. Lester, Dennis A. Dougherty and Sarah C. R. Lummis
Molecular Pharmacology April 2011, 79 (4) 742-748; DOI: https://doi.org/10.1124/mol.110.069583
Stephan A. Pless
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Ariele P. Hanek
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Kerry L. Price
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Joseph W. Lynch
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Henry A. Lester
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Dennis A. Dougherty
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Sarah C. R. Lummis
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Abstract

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.

Footnotes

  • 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.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.069583.

  • ABBREVIATIONS:

    GlyR
    glycine receptor
    5-HT3
    5-hydroxytryptamine3
    nAChR
    nicotinic acetylcholine receptor
    AChBP
    acetylcholine-binding protein
    tRNA
    transfer RNA
    WT
    wild type.

  • Received October 22, 2010.
  • Accepted January 4, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

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

Stephan A. Pless, Ariele P. Hanek, Kerry L. Price, Joseph W. Lynch, Henry A. Lester, Dennis A. Dougherty and Sarah C. R. Lummis
Molecular Pharmacology April 1, 2011, 79 (4) 742-748; DOI: https://doi.org/10.1124/mol.110.069583

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Research ArticleArticle

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

Stephan A. Pless, Ariele P. Hanek, Kerry L. Price, Joseph W. Lynch, Henry A. Lester, Dennis A. Dougherty and Sarah C. R. Lummis
Molecular Pharmacology April 1, 2011, 79 (4) 742-748; DOI: https://doi.org/10.1124/mol.110.069583
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