ArticleCell research2023
Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers.
Article in Cell research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 55 citations in OpenAlex.
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- G protein selectivity in group I metabotropic glutamate receptors.Science advances · 2026Article
- Structural characterization of kappa-opioid receptor dimer in complex with two G proteins.Nature communications · 2026Article
- Subtype-dependent arrestin engagement of the metabotropic glutamate receptors.Nature communications · 2026Article
- Structural and Energetic Determinants of Sweet Protein Recognition: Mechanistic Insights into Thaumatin Binding to the Human T1R2/T1R3 Receptor.International journal of molecular sciences · 2026Article
- Ligand Binding Dynamics of Ion Channels and GPCRs Using Single-Molecule Fluorescence.Annual review of biophysics · 2026Review
- Cryo-EM Structures of Brain-Derived G Protein-Coupled Receptors: The First Direct Visualization from Mammalian Brain Tissue.bioRxiv : the preprint server for biology · 2026Article
- CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling.Nature communications · 2026Article
- Allosteric activation of the glutamate receptor mGlu2 by the serotonin receptor 5-HTNature communications · 2026Article
- GPCR Heterodimers: Implications for Biased Signaling.Handbook of experimental pharmacology · 2026Review
- Unveiling the mechanistic links between plasticizers and gastric cancer via network toxicology and molecular docking approaches.BMC pharmacology & toxicology · 2025Article
- Structural Basis of GABAAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Domain coupling in activation of a family C GPCR.Nature chemical biology · 2025Article
- Unveiling the molecular mechanism of GProtein science : a publication of the Protein Society · 2025Article
- Metabotropic glutamate receptor homo- and heterodimers exhibit distinct responses to orthosteric and allosteric ligands.Molecular pharmacology · 2025Article
- mGlu2 Receptors in the Basal Ganglia: A New Frontier in Addiction Therapy.Frontiers in bioscience (Landmark edition) · 2025Review
- Molecular basis of β-arrestin coupling to the metabotropic glutamate receptor mGlu3.Nature chemical biology · 2025Article
- The structural basis of the G protein-coupled receptor and ion channel axis.Current research in structural biology · 2025Review
- Single-molecule localization microscopy as a tool to quantify di/oligomerization of receptor tyrosine kinases and G protein-coupled receptors.Molecular pharmacology · 2025Review
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Authors and funding
11 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus.
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