Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2008 Oct 22;2843:10937-42. doi: 10.1523/JNEUROSCI.2540-08.2008.
Show Gene links
Show Anatomy links
A cation-pi interaction in the binding site of the glycine receptor is mediated by a phenylalanine residue.
Pless SA
,
Millen KS
,
Hanek AP
,
Lynch JW
,
Lester HA
,
Lummis SC
,
Dougherty DA
.
???displayArticle.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 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.
Beene,
Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
2002, Pubmed,
Xenbase
Beene,
Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
2002,
Pubmed
,
Xenbase
Beene,
Unnatural amino acid mutagenesis in mapping ion channel function.
2003,
Pubmed
,
Xenbase
Beene,
Tyrosine residues that control binding and gating in the 5-hydroxytryptamine3 receptor revealed by unnatural amino acid mutagenesis.
2004,
Pubmed
,
Xenbase
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
De Saint Jan,
Activation of human alpha1 and alpha2 homomeric glycine receptors by taurine and GABA.
2001,
Pubmed
,
Xenbase
Dougherty,
Unnatural amino acids as probes of protein structure and function.
2000,
Pubmed
Grudzinska,
The beta subunit determines the ligand binding properties of synaptic glycine receptors.
2005,
Pubmed
Harvey,
GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.
2004,
Pubmed
Kearney,
Dose-response relations for unnatural amino acids at the agonist binding site of the nicotinic acetylcholine receptor: tests with novel side chains and with several agonists.
1996,
Pubmed
,
Xenbase
Laube,
Modulation of glycine receptor function: a novel approach for therapeutic intervention at inhibitory synapses?
2002,
Pubmed
Le Novère,
The Ligand Gated Ion Channel database: an example of a sequence database in neuroscience.
2001,
Pubmed
Legendre,
The glycinergic inhibitory synapse.
2001,
Pubmed
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed
Mecozzi,
Cation-pi interactions in aromatics of biological and medicinal interest: electrostatic potential surfaces as a useful qualitative guide.
1996,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Mu,
Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?
2003,
Pubmed
Nowak,
In vivo incorporation of unnatural amino acids into ion channels in Xenopus oocyte expression system.
1998,
Pubmed
,
Xenbase
Padgett,
Unnatural amino acid mutagenesis of the GABA(A) receptor binding site residues reveals a novel cation-pi interaction between GABA and beta 2Tyr97.
2007,
Pubmed
,
Xenbase
Pless,
Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.
2007,
Pubmed
,
Xenbase
Price,
The role of tyrosine residues in the extracellular domain of the 5-hydroxytryptamine3 receptor.
2004,
Pubmed
,
Xenbase
Rajendra,
The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding element.
1995,
Pubmed
Reeves,
Prediction of 5-HT3 receptor agonist-binding residues using homology modeling.
2003,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Thompson,
Locating an antagonist in the 5-HT3 receptor binding site using modeling and radioligand binding.
2005,
Pubmed
Thompson,
The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors.
2007,
Pubmed
,
Xenbase
Unwin,
Acetylcholine receptor channel imaged in the open state.
1995,
Pubmed
Vafa,
Identification of a new ligand binding domain in the alpha1 subunit of the inhibitory glycine receptor.
1999,
Pubmed
Vandenberg,
Antagonism of ligand-gated ion channel receptors: two domains of the glycine receptor alpha subunit form the strychnine-binding site.
1992,
Pubmed
Vandenberg,
Distinct agonist- and antagonist-binding sites on the glycine receptor.
1992,
Pubmed
Yang,
Tropisetron modulation of the glycine receptor: femtomolar potentiation and a molecular determinant of inhibition.
2007,
Pubmed
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed
