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.
Protein Sci
2009 Nov 01;1811:2371-83. doi: 10.1002/pro.247.
Show Gene links
Show Anatomy links
Structural model of rho1 GABAC receptor based on evolutionary analysis: Testing of predicted protein-protein interactions involved in receptor assembly and function.
Adamian L, Gussin HA, Tseng YY, Muni NJ, Feng F, Qian H, Pepperberg DR, Liang J.
???displayArticle.abstract???
The homopentameric rho1 GABA(C) receptor is a ligand-gated ion channel with a binding pocket for gamma-aminobutyric acid (GABA) at the interfaces of N-terminal extracellular domains. We combined evolutionary analysis, structural modeling, and experimental testing to study determinants of GABA(C) receptor assembly and channel gating. We estimated the posterior probability of selection pressure at amino acid residue sites measured as omega-values and built a comparative structural model, which identified several polar residues under strong selection pressure at the subunit interfaces that may form intersubunit hydrogen bonds or salt bridges. At three selected sites (R111, T151, and E55), mutations disrupting intersubunit interactions had strong effects on receptor folding, assembly, and function. We next examined the role of a predicted intersubunit salt bridge for residue pair R158-D204. The mutant R158D, where the positively charged residue is replaced by a negatively charged aspartate, yielded a partially degraded receptor and lacked membrane surface expression. The membrane surface expression was rescued by the double mutant R158D-D204R, where positive and negative charges are switched, although the mutant receptor was inactive. The single mutants R158A, D204R, and D204A exhibited diminished activities and altered kinetic profiles with fast recovery kinetics, suggesting that R158-D204 salt bridge perhaps stabilizes the open state of the GABA(C) receptor. Our results emphasize the functional importance of highly conserved polar residues at the protein-protein interfaces in GABA(C) rho1 receptors and demonstrate how the integration of computational and experimental approaches can aid discovery of functionally important interactions.
Abdel-Halim,
A molecular basis for agonist and antagonist actions at GABA(C) receptors.
2008, Pubmed
Abdel-Halim,
A molecular basis for agonist and antagonist actions at GABA(C) receptors.
2008,
Pubmed Amin,
Homomeric rho 1 GABA channels: activation properties and domains.
1994,
Pubmed
,
Xenbase Bocquet,
X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation.
2009,
Pubmed Bourne,
Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.
2005,
Pubmed Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed Caffrey,
PFAAT version 2.0: a tool for editing, annotating, and analyzing multiple sequence alignments.
2007,
Pubmed Carland,
Charged residues at the 2' position of human GABAC rho 1 receptors invert ion selectivity and influence open state probability.
2004,
Pubmed Celie,
Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors.
2005,
Pubmed Celie,
Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures.
2004,
Pubmed Chebib,
GABAC receptor ion channels.
2004,
Pubmed Cole,
The Jpred 3 secondary structure prediction server.
2008,
Pubmed Corringer,
Nicotinic receptors at the amino acid level.
2000,
Pubmed Cromer,
Anxiety over GABA(A) receptor structure relieved by AChBP.
2002,
Pubmed Dellisanti,
Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution.
2007,
Pubmed Edelsbrunner,
On the definition and the construction of pockets in macromolecules.
1996,
Pubmed Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed Harrison,
Molecular modeling of the GABA(C) receptor ligand-binding domain.
2006,
Pubmed Harrison,
Locating the carboxylate group of GABA in the homomeric rho GABA(A) receptor ligand-binding pocket.
2006,
Pubmed Henchman,
Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulation.
2003,
Pubmed Hilf,
Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.
2009,
Pubmed Johnston,
GABAc receptors: relatively simple transmitter -gated ion channels?
1996,
Pubmed Karlin,
Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins.
1995,
Pubmed Kusama,
Mutagenesis of the GABA rho 1 receptor alters agonist affinity and channel gating.
1994,
Pubmed
,
Xenbase Larkin,
Clustal W and Clustal X version 2.0.
2007,
Pubmed Lecompte,
Multiple alignment of complete sequences (MACS) in the post-genomic era.
2001,
Pubmed Liang,
Analytical shape computation of macromolecules: II. Inaccessible cavities in proteins.
1998,
Pubmed Nei,
Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions.
1986,
Pubmed Osolodkin,
Molecular modeling of ligand-receptor interactions in GABA C receptor.
2009,
Pubmed Qian,
A comparison of GABAC and rho subunit receptors from the white perch retina.
1997,
Pubmed
,
Xenbase Reeves,
The molecular basis of the structure and function of the 5-HT3 receptor: a model ligand-gated ion channel (review).
2002,
Pubmed Rose,
Hydrophobicity of amino acid residues in globular proteins.
1985,
Pubmed Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed Sarto-Jackson,
Identification of amino acid residues important for assembly of GABA receptor alpha1 and gamma2 subunits.
2006,
Pubmed Sedelnikova,
Mapping the rho1 GABA(C) receptor agonist binding pocket. Constructing a complete model.
2005,
Pubmed Sine,
Recent advances in Cys-loop receptor structure and function.
2006,
Pubmed Smit,
A glia-derived acetylcholine-binding protein that modulates synaptic transmission.
2001,
Pubmed Speranskiy,
Homology modeling and molecular dynamics simulations of the glycine receptor ligand binding domain.
2007,
Pubmed Tasneem,
Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels.
2005,
Pubmed Thompson,
CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
1994,
Pubmed Torres,
Identification of a tyrosine in the agonist binding site of the homomeric rho1 gamma-aminobutyric acid (GABA) receptor that, when mutated, produces spontaneous opening.
2002,
Pubmed
,
Xenbase Tseng,
Are residues in a protein folding nucleus evolutionarily conserved?
2004,
Pubmed Tseng,
Estimation of amino acid residue substitution rates at local spatial regions and application in protein function inference: a Bayesian Monte Carlo approach.
2006,
Pubmed Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed Vu,
Activation of membrane receptors by a neurotransmitter conjugate designed for surface attachment.
2005,
Pubmed
,
Xenbase Wang,
Establishing an ion pair interaction in the homomeric rho1 gamma-aminobutyric acid type A receptor that contributes to the gating pathway.
2007,
Pubmed
,
Xenbase Wible,
Cloning and expression of a novel K+ channel regulatory protein, KChAP.
1998,
Pubmed
,
Xenbase Yang,
PAML 4: phylogenetic analysis by maximum likelihood.
2007,
Pubmed Yang,
PAML: a program package for phylogenetic analysis by maximum likelihood.
1997,
Pubmed Yang,
Maximum-likelihood estimation of phylogeny from DNA sequences when substitution rates differ over sites.
1993,
Pubmed Zhang,
Structural determinants for antagonist pharmacology that distinguish the rho1 GABAC receptor from GABAA receptors.
2008,
Pubmed
,
Xenbase Zhang,
Agonist- and antagonist-induced conformational changes of loop F and their contributions to the rho1 GABA receptor function.
2009,
Pubmed
,
Xenbase Zhang,
Structure and function of GABA(C) receptors: a comparison of native versus recombinant receptors.
2001,
Pubmed
