ArticleProceedings of the National Academy of Sciences of the United States of America2002
Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 107 citations in OpenAlex.
- Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease.Pharmacological reviews · 2022Review
- Review
- Class A and C GPCR Dimers in Neurodegenerative Diseases.Current neuropharmacology · 2022Review
- Cation-π Interactions and their Functional Roles in Membrane Proteins.Journal of molecular biology · 2021Review
- Structural insights into the activation initiation of full-length mGlu1.Protein & cell · 2021Article
- Structural Dynamics of Glutamate Signaling Systems by smFRET.Biophysical journal · 2020Review
- Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors.Molecules (Basel, Switzerland) · 2019Review
- Organization and functions of mGlu and GABANature · 2016Review
- Outside-in signaling--a brief review of GPCR signaling with a focus on the Drosophila GPCR family.Journal of cell science · 2015Review
- Blocking metabotropic glutamate receptor subtype 7 (mGlu7) via the Venus flytrap domain (VFTD) inhibits amygdala plasticity, stress, and anxiety-related behavior.The Journal of biological chemistry · 2014Article
- Dimers of G-protein coupled receptors as versatile storage and response units.International journal of molecular sciences · 2014Article
- Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations.Journal of chemical information and modeling · 2013Article
- Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Gαo is required for L-canavanine detection in Drosophila.PloS one · 2013Article
- Distinct roles of metabotropic glutamate receptor dimerization in agonist activation and G-protein coupling.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Structure and ligand recognition of class C GPCRs.Acta pharmacologica Sinica · 2012Review
- Interdomain movements in metabotropic glutamate receptor activation.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Metabotropic glutamate receptors: from the workbench to the bedside.Neuropharmacology · 2011Review
- Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential.Neuropharmacology · 2011Review
- Allosteric modulation of metabotropic glutamate receptors.Advances in pharmacology (San Diego, Calif.) · 2011Review
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ca2+, pheromones, sweet taste compounds, and the main neurotransmitters glutamate and gamma-aminobutyric acid activate G protein-coupled receptors (GPCRs) that constitute the GPCR family 3. These receptors are dimers, and each subunit has a large extracellular domain called a Venus flytrap module (VFTM), where agonists bind. This module is connected to a heptahelical domain that activates G proteins. Recently, the structure of the dimer of mGlu1 VFTMs revealed two important conformational changes resulting from glutamate binding. First, agonists can stabilize a closed state of at least one VFTM in the dimer. Second, the relative orientation of the two VFTMs in the dimer is different in the presence of glutamate, such that their C-terminal ends (which are connected to the G protein-activating heptahelical domain) become closer by more than 20 A. This latter change in orientation has been proposed to play a key role in receptor activation. To elucidate the respective role of VFTM closure and the change in orientation of the VFTMs in family 3 GPCR activation, we analyzed the mechanism of action of the mGlu8 receptor antagonists ACPT-II and MAP4. Molecular modeling studies suggest that these two compounds prevent the closure of the mGlu8 VFTM because of ionic and steric hindrance, respectively. We show here that the replacement of the residues responsible for these hindrances (Asp-309 and Tyr-227, respectively) by Ala allows ACPT-II or MAP4 to fully activate the receptors. These data are consistent with the requirement of the VFTM closure for family 3 GPCR activation.
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