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A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Pless, Stephan
  • Kat S Millen
  • Ariele P Hanek
  • Joseph W Lynch
  • Henry A Lester
  • Sarah C R Lummis
  • Dennis A Dougherty

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 EC(50) 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.

OriginalsprogEngelsk
TidsskriftThe Journal of neuroscience : the official journal of the Society for Neuroscience
Vol/bind28
Udgave nummer43
Sider (fra-til)10937-42
Antal sider6
ISSN0270-6474
DOI
StatusUdgivet - 22 okt. 2008

ID: 122597853