ArticleNature chemical biology2025
Domain coupling in activation of a family C GPCR.
Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Structural basis of active state coupling of metabotropic glutamate receptor 8 to beta-arrestins.Nature communications · 2026Article
- Structural basis for modulation of group III mGlu receptors by transsynaptic interactions.Science advances · 2026Article
- N-Glycosylation of mGluR6 Modulates Receptor Cell-Surface Transport, G-Protein Coupling, and Interactions With Synaptic Adhesion Molecules.Journal of molecular neuroscience : MN · 2026Article
- 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
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling.Nature communications · 2026Article
- Domain coupling in activation of a family C GPCR.Nature chemical biology · 2025Article
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Abstract
The G protein-coupled metabotropic glutamate receptors form homodimers and heterodimers with highly diverse responses to glutamate and varying physiological functions. We employ molecular dynamics, single-molecule spectroscopy and hydrogen-deuterium exchange to dissect the activation pathway triggered by glutamate. We find that activation entails multiple loosely coupled steps, including formation of an agonist-bound, pre-active intermediate whose transition to active conformations forms dimerization interface contacts that set efficacy. The agonist-bound receptor populates at least two additional intermediates en route to G protein-coupling conformations. Sequential transitions into these states act as 'gates', which attenuate the effects of glutamate. Thus, the agonist-bound receptor is remarkably dynamic, with low occupancy of G protein-coupling conformations, providing considerable headroom for modulation by allosteric ligands. Sequence variation within the dimerization interface, as well as altered conformational coupling in receptor heterodimers, may contribute to precise decoding of glutamate signals over broad spatial and temporal scales.
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