A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor

Chem Biol. 2005 Sep;12(9):993-7. doi: 10.1016/j.chembiol.2005.06.012.


GABA(C) (rho) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which includes nicotinic acetylcholine (nACh), 5-HT(3), and glycine receptors. As in other members of this family, the agonist binding site of GABA(C) receptors is rich in aromatic amino acids, but while other receptors bind agonist through a cation-pi interaction to a tryptophan, the GABA(C) binding site has tyrosine at the aligning positions. Incorporating a series of tyrosine derivatives at position 198 using unnatural amino acid mutagenesis reveals a clear correlation between the cation-pi binding ability of the side chain and EC(50) for receptor activation, thus demonstrating a cation-pi interaction between a tyrosine side chain and a neurotransmitter. Comparisons among four homologous receptors show variations in cation-pi binding energies that reflect the nature of the cationic center of the agonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Cations
  • Models, Molecular
  • Mutagenesis
  • Protein Conformation
  • Receptors, GABA / chemistry
  • Receptors, GABA / metabolism*
  • Tyrosine / metabolism*


  • Cations
  • GABA-C receptor
  • Receptors, GABA
  • Tyrosine