ArticleMolecular pharmacology2011
Three arginines in the GABAA receptor binding pocket have distinct roles in the formation and stability of agonist- versus antagonist-bound complexes.
Article in Molecular pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
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- Computational drug repositioning approach to predict multi-target therapeutics for epilepsy.Scientific reports · 2025Article
- Structural insights into the interaction between gabazine (SR-95531) andJournal of pesticide science · 2022Article
- Multiquantum Chemical Exchange Saturation Transfer NMR to Quantify Symmetrical Exchange: Application to Rotational Dynamics of the Guanidinium Group in Arginine Side Chains.The journal of physical chemistry letters · 2020Article
- Crystal structure of diamondback moth ryanodine receptor Repeat34 domain reveals insect-specific phosphorylation sites.BMC biology · 2019Article
- Concatenated γ-aminobutyric acid type A receptors revisited: Finding order in chaos.The Journal of general physiology · 2019Article
- Structure of a human synaptic GABANature · 2018Article
- AJournal of biomolecular NMR · 2017Article
- Loop G in the GABAThe Journal of physiology · 2017Article
- A role for loop G in the β1 strand in GABAA receptor activation.The Journal of physiology · 2016Article
- Epileptic encephalopathy de novo GABRB mutations impair γ-aminobutyric acid type A receptor function.Annals of neurology · 2016Article
- Molecular basis for convergent evolution of glutamate recognition by pentameric ligand-gated ion channels.Scientific reports · 2015Article
- A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors.The Journal of general physiology · 2014Article
- α1F64 Residue at GABA(A) receptor binding site is involved in gating by influencing the receptor flipping transitions.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Principles of agonist recognition in Cys-loop receptors.Frontiers in physiology · 2014Review
- Multiple tyrosine residues at the GABA binding pocket influence surface expression and mediate kinetics of the GABAA receptor.Journal of neurochemistry · 2013Article
- Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Binding of the agonist GABA to the GABA(A) receptor causes channel gating, whereas competitive antagonists that bind at the same site do not. The details of ligand binding are not well understood, including which residues interact directly with ligands, maintain the structure of the binding pocket, or transduce the action of binding into opening of the ion channel gate. Recent work suggests that the amine group of the GABA molecule may form a cation-π bond with residues in a highly conserved "aromatic box" within the binding pocket. Although interactions with the carboxyl group of GABA remain unknown, three positively charged arginines (α(1)Arg67, α(1)Arg132, and β(2)Arg207) just outside of the aromatic box are likely candidates. To explore their roles in ligand binding, we individually mutated these arginines to alanine and measured the effects on microscopic ligand binding/unbinding rates and channel gating. The mutations α(1)R67A or β(2)R207A slowed agonist binding and sped unbinding with little effect on gating, demonstrating that these arginines are critical for both formation and stability of the agonist-bound complex. In addition, α(1)R67A sped binding of the antagonist 2-(3-carboxypropyl)-3-amino-6-(4 methoxyphenyl)pyridazinium bromide (SR-95531), indicating that this arginine poses a barrier to formation of the antagonist-bound complex. In contrast, β(2)R207A and α(1)R132A sped antagonist unbinding, indicating that these arginines stabilize the antagonist-bound state. α(1)R132A also conferred a new long-lived open state, indicating that this arginine influences the channel gate. Thus, each of these arginines plays a unique role in determining interactions with agonists versus antagonists and with the channel gate.
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