ArticleProtein science : a publication of the Protein Society2009
Structural model of rho1 GABAC receptor based on evolutionary analysis: Testing of predicted protein-protein interactions involved in receptor assembly and function.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 17 citations in OpenAlex.
- A hydrophobic area of the GABA ρ₁ receptor containing phenylalanine 124 influences both receptor activation and deactivation.Journal of molecular neuroscience : MN · 2015Article
- Design, Synthesis, and Pharmacological Evaluation of Fluorescent and Biotinylated Antagonists of ρ1 GABAC Receptors.ACS medicinal chemistry letters · 2013Article
- Differentiating enantioselective actions of GABOB: a possible role for threonine 244 in the binding site of GABA(C) ρ(1) receptors.ACS chemical neuroscience · 2012Article
- Classification of protein functional surfaces using structural characteristics.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Robust photoregulation of GABA(A) receptors by allosteric modulation with a propofol analogue.Nature communications · 2012Article
- Ionic channels as targets for drug design: a review on computational methods.Pharmaceutics · 2011Article
- Subunit-specific polyclonal antibody targeting human ρ1 GABA(C) receptor.Experimental eye research · 2011Article
- New insights into the GABA(A) receptor structure and orthosteric ligand binding: receptor modeling guided by experimental data.Proteins · 2011Article
- Lipid-binding surfaces of membrane proteins: evidence from evolutionary and structural analysis.Biochimica et biophysica acta · 2011Article
- Evolutionary approach to predicting the binding site residues of a protein from its primary sequence.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology.ACS medicinal chemistry letters · 2011Article
- Neurochemicals for the investigation of GABA(C) receptors.Neurochemical research · 2010Review
- Structure-function study of the fourth transmembrane segment of the GABAρ1 receptor.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- GABAC receptor binding of quantum-dot conjugates of variable ligand valency.Bioconjugate chemistry · 2010Article
- Identification of novel specific allosteric modulators of the glycine receptor using phage display.The Journal of biological chemistry · 2010Article
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8 authors at 1 institution in 1 country.
Funding
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.
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