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
2011 Aug 24;3134:12371-6. doi: 10.1523/JNEUROSCI.1610-11.2011.
Show Gene links
Show Anatomy links
Two amino acid residues contribute to a cation-π binding interaction in the binding site of an insect GABA receptor.
Lummis SC
,
McGonigle I
,
Ashby JA
,
Dougherty DA
.
???displayArticle.abstract???
Cys-loop receptor binding sites characteristically possess an "aromatic box," where several aromatic amino acid residues surround the bound ligand. A cation-π interaction between one of these residues and the natural agonist is common, although the residue type and location are not conserved. Even in the closely related vertebrate GABA(A) and GABA(C) receptors, residues in distinct locations perform this role: in GABA(A) receptors, a Tyr residue in loop A forms a cation-π interaction with GABA, while in GABA(C) receptors it is a loop B residue. GABA-activated Cys-loop receptors also exist in invertebrates, where they have distinct pharmacologies and are the target of a range of pesticides. Here we examine the location of GABA in an insect binding site by incorporating a series of fluorinated Phe derivatives into the receptor binding pocket using unnatural amino acid mutagenesis, and evaluating the resulting receptors when expressed in Xenopus oocytes. A homology model suggests that two aromatic residues (in loops B and C) are positioned such that they could contribute to a cation-π interaction with the primary ammonium of GABA, and the data reveal a clear correlation between the GABA EC(50) and the cation-π binding ability both at Phe206 (loop B) and Tyr254 (loop C), demonstrating for the first time the contribution of two aromatic residues to a cation-π interaction in a Cys-loop receptor.
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,
Tyrosine residues that control binding and gating in the 5-hydroxytryptamine3 receptor revealed by unnatural amino acid mutagenesis.
2004,
Pubmed
,
Xenbase
Beene,
Unnatural amino acid mutagenesis in mapping ion channel function.
2003,
Pubmed
,
Xenbase
Belelli,
Interaction of positive allosteric modulators with human and Drosophila recombinant GABA receptors expressed in Xenopus laevis oocytes.
1996,
Pubmed
,
Xenbase
Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Dougherty,
Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp.
1996,
Pubmed
Dougherty,
Unnatural amino acids as probes of protein structure and function.
2000,
Pubmed
Harrison,
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
2006,
Pubmed
Harrison,
Molecular modeling of the GABA(C) receptor ligand-binding domain.
2006,
Pubmed
Hilf,
X-ray structure of a prokaryotic pentameric ligand-gated ion channel.
2008,
Pubmed
Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed
Hosie,
Alternative splicing of a Drosophila GABA receptor subunit gene identifies determinants of agonist potency.
2001,
Pubmed
,
Xenbase
Hosie,
Allosteric modulation of an expressed homo-oligomeric GABA-gated chloride channel of Drosophila melanogaster.
1996,
Pubmed
,
Xenbase
Hosie,
Agonist pharmacology of two Drosophila GABA receptor splice variants.
1996,
Pubmed
,
Xenbase
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
Lummis,
A cation-pi binding interaction with a tyrosine in the binding site of the GABAC receptor.
2005,
Pubmed
McGonigle,
Molecular characterization of agonists that bind to an insect GABA receptor.
2010,
Pubmed
,
Xenbase
McGurk,
The effect of a transmembrane amino acid on etomidate sensitivity of an invertebrate GABA receptor.
1998,
Pubmed
,
Xenbase
Millar,
Stable expression of a functional homo-oligomeric Drosophila GABA receptor in a Drosophila cell line.
1994,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
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,
A cation-π interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists.
2011,
Pubmed
,
Xenbase
Pless,
Conformational variability of the glycine receptor M2 domain in response to activation by different agonists.
2007,
Pubmed
,
Xenbase
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Shi,
FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.
2001,
Pubmed
Thompson,
Loop B is a major structural component of the 5-HT3 receptor.
2008,
Pubmed
Unwin,
Acetylcholine receptor channel imaged in the open state.
1995,
Pubmed
Zhang,
A unique amino acid of the Drosophila GABA receptor with influence on drug sensitivity by two mechanisms.
1994,
Pubmed
Zhong,
From ab initio quantum mechanics to molecular neurobiology: a cation-pi binding site in the nicotinic receptor.
1998,
Pubmed