ArticleProceedings of the National Academy of Sciences of the United States of America2015
Allosteric and hyperekplexic mutant phenotypes investigated on an α1 glycine receptor transmembrane structure.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Structural basis for domain coupling in heteromeric glycine receptors revealed by an atypical allosteric agonist.Science advances · 2026Article
- Gating mechanism of the human α1β GlyR by glycine.Structure (London, England : 1993) · 2024Article
- Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations.The journal of physical chemistry. B · 2024Article
- An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies.Nature communications · 2023Article
- Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies.Pharmacological reviews · 2022Review
- Drosophila functional screening of de novo variants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases.Cell reports · 2022Article
- Article
- Effects of Interleukin-1β in Glycinergic Transmission at the Central Amygdala.Frontiers in pharmacology · 2021Article
- Structural basis of neurosteroid anesthetic action on GABANature communications · 2018Article
- X-Ray Crystallographic Studies for Revealing Binding Sites of General Anesthetics in Pentameric Ligand-Gated Ion Channels.Methods in enzymology · 2018Article
- Article
- Crystal structures of a GABANature structural & molecular biology · 2017Article
- A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation.Neuropharmacology · 2017Article
- The GlyR Extracellular β8-β9 Loop - A Functional Determinant of Agonist Potency.Frontiers in molecular neuroscience · 2017Article
- Genome-wide analysis of structural variants reveals genetic differences in Chinese pigs.PloS one · 2017Article
- Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors.Molecular pharmacology · 2016Review
- Functional Human α7 Nicotinic Acetylcholine Receptor (nAChR) Generated from Escherichia coli.The Journal of biological chemistry · 2016Article
- Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain.The Journal of clinical investigation · 2016Article
- Interaction of three-finger proteins from snake venoms and from mammalian brain with the cys-loop receptors and their models.Doklady. Biochemistry and biophysics · 2016Article
- Human Secreted Ly-6/uPAR Related Protein-1 (SLURP-1) Is a Selective Allosteric Antagonist of α7 Nicotinic Acetylcholine Receptor.PloS one · 2016Article
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11 authors.
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Abstract
The glycine receptor (GlyR) is a pentameric ligand-gated ion channel (pLGIC) mediating inhibitory transmission in the nervous system. Its transmembrane domain (TMD) is the target of allosteric modulators such as general anesthetics and ethanol and is a major locus for hyperekplexic congenital mutations altering the allosteric transitions of activation or desensitization. We previously showed that the TMD of the human α1GlyR could be fused to the extracellular domain of GLIC, a bacterial pLGIC, to form a functional chimera called Lily. Here, we overexpress Lily in Schneider 2 insect cells and solve its structure by X-ray crystallography at 3.5 Å resolution. The TMD of the α1GlyR adopts a closed-channel conformation involving a single ring of hydrophobic residues at the center of the pore. Electrophysiological recordings show that the phenotypes of key allosteric mutations of the α1GlyR, scattered all along the pore, are qualitatively preserved in this chimera, including those that confer decreased sensitivity to agonists, constitutive activity, decreased activation kinetics, or increased desensitization kinetics. Combined structural and functional data indicate a pore-opening mechanism for the α1GlyR, suggesting a structural explanation for the effect of some key hyperekplexic allosteric mutations. The first X-ray structure of the TMD of the α1GlyR solved here using GLIC as a scaffold paves the way for mechanistic investigation and design of allosteric modulators of a human receptor.
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