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| Title | Structural basis of active state coupling of metabotropic glutamate receptor 8 to beta-arrestins. |
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| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Sep 10, 2026 |
 Authors | Dagan C Marx / Kevin Huynh / Alberto J Gonzalez-Hernandez / Alexa Strauss / Carlos Rico / Pamela N Gallo / Sheida Sharghi Moshtaghin / Anisul Arefin / Johannes Broichhagen / David Eliezer / George Khelashvili / Joshua Levitz /   |
| PubMed Abstract | Metabotropic glutamate receptors (mGluRs) are prototypical, dimeric family C G protein-coupled receptors (GPCR) that perform crucial modulatory roles throughout the nervous system. While mGluR ...Metabotropic glutamate receptors (mGluRs) are prototypical, dimeric family C G protein-coupled receptors (GPCR) that perform crucial modulatory roles throughout the nervous system. While mGluR activation and signaling through G proteins has been studied extensively, how these receptors interact with and are desensitized by β-arrestins (β-arrs) is not well understood. Here, we use an integrative biophysical and structural approach to probe the coupling of mGluR8 and β-arrs. Using negative stain electron microscopy (EM), we identify tail- and core-bound orientations and stoichiometries of mGluR8/β-arr complexes. Cryo-EM structures of mGluR8 alone or bound to either G proteins or β-arr1 reveal mGluR8 active states with transducer-specific differences. The mGluR8/β-arr structure shows a distinct complex orientation compared to other GPCR/β-arr structures which supports a steric mechanism of mGluR desensitization involving interactions with both subunits and the lipid bilayer. Coupling of mGluR8 to β-arr1 in an active-like conformation is verified by live-cell and single molecule FRET analysis. Finally, molecular dynamics simulations further define the positioning and dynamics of mGluR8-bound β-arr1 and the importance of critical mGluR8 residues for stabilizing β-arr1 complexes. Together, our data provide a framework for agonist-driven family C GPCR/β-arr coupling. |
 External links | Nat Commun / PubMed:42722693 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.76 - 6.18 Å |
| Structure data | EMDB-49153, PDB-9n8y: EMDB-49154, PDB-9n8z: EMDB-72398, PDB-9y1m: EMDB-72399, PDB-9y1n:  EMDB-78690: Non-uniform refinement consensus map of mGluR8 bound to agonist, PAM, and G protein heterotrimer  EMDB-78692: Local refinement of LBD of mGluR8 bound to agonist, PAM, and G proteins  EMDB-78693: Local refinement of agonist-bound mGluR8 CRD and TMD in complex to G protein heterotrimer  EMDB-78695: Local Refinement of mGluR8 TMD and G protein heterotrimer in complex  EMDB-78696: Local Refinement of G protein heterotrimer bound to scFv14 when in complex with active mGluR8  EMDB-78722: Local Refinement of mGluR8 LBD when in complex with beta-arrestin-1  EMDB-78723: Local refinement of agonist/PAM bound mGluR8 chain A LBD and CRD when in complex with beta-arrestin-1  EMDB-78724: Consensus non-uniform refinement map of agonist/PAM bound mGluR8 in complex with beta-arrestin-1  EMDB-78725: Local Refinement of agonist/PAM bound mGluR8 chain B CRD and TMD when in complex with beta-arrestin-1 |
| Chemicals |  ChemComp-E7P:  PDB-1bwg: |
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 Keywords | MEMBRANE PROTEIN / GPCR / metabotropic glutamate receptor / synaptic protein / signaling protein |
homo sapiens (human)
mus musculus (house mouse)