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- PDB-9y1n: Cryo EM Structure of Full lengthmGluR8 Bound to Agonist L-AP4 and... -

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Basic information

Entry
Database: PDB / ID: 9y1n
TitleCryo EM Structure of Full lengthmGluR8 Bound to Agonist L-AP4 and PAM VU6005649 in complex with G proteins
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Metabotropic glutamate receptor 8
  • scFv-14
KeywordsMEMBRANE PROTEIN / GPCR / metabotropic glutamate receptor / synaptic protein / signaling protein
Function / homology
Function and homology information


group III metabotropic glutamate receptor activity / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / visual perception / regulation of synaptic transmission, glutamatergic / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration ...group III metabotropic glutamate receptor activity / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / visual perception / regulation of synaptic transmission, glutamatergic / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting dopamine receptor signaling pathway / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / regulation of G protein-coupled receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / establishment of mitotic spindle orientation / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / GDP binding / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / cell division / spindle pole / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / ciliary basal body / GTPase binding / midbody / G protein activity / cell cortex / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / cytoplasmic side of plasma membrane / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / centrosome / GTPase activity / GTP binding / synapse / protein-containing complex binding / magnesium ion binding / signal transduction / extracellular exosome / membrane / nucleus
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 8 / GPCR, family 3, metabotropic glutamate receptor / : / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site ...GPCR, family 3, metabotropic glutamate receptor 8 / GPCR, family 3, metabotropic glutamate receptor / : / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein alpha subunit, group I / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / (2S)-2-amino-4-phosphonobutanoic acid / Metabotropic glutamate receptor 8 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.18 Å
AuthorsMarx, D.C. / Levitz, J.T.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32GM148001 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS129904 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS129320 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis of active state coupling of metabotropic glutamate receptor 8 to beta-arrestins.
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 / ...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 /
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.
History
DepositionAug 29, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 30, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 30, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Metabotropic glutamate receptor 8
B: Metabotropic glutamate receptor 8
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
D: scFv-14
E: Guanine nucleotide-binding protein G(i) subunit alpha-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)304,4629
Polymers303,7396
Non-polymers7233
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules CEG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Homo sapiens (human) / References: UniProt: P59768
#4: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Homo sapiens (human)
References: UniProt: P63096, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39286.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Homo sapiens (human) / References: UniProt: P62873

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Protein / Antibody , 2 types, 3 molecules ABD

#1: Protein Metabotropic glutamate receptor 8 / mGluR8


Mass: 94195.492 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM8, GPRC1H, MGLUR8 / Production host: Homo sapiens (human) / References: UniProt: O00222
#3: Antibody scFv-14


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)

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Non-polymers , 2 types, 3 molecules

#6: Chemical ChemComp-E7P / (2S)-2-amino-4-phosphonobutanoic acid


Mass: 183.100 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10NO5P / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM
#7: Chemical ChemComp-A1BWG / (3P,8S)-3-(2,3-difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine


Mass: 357.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H12F5N3O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Metabotropic Glutamate receptor bound to G proteins alpha i-1, beta-1, and gamma-2 in the presence of agonist and PAM and scFv14COMPLEX#1-#50RECOMBINANT
2G protein heterotrimer bound to scFv14COMPLEX#2-#51RECOMBINANT
3mGluR8 homodimer bound to agonist and PAMCOMPLEX#11RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.302 MDaNO
21.115 MDaNO
310.188 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenConc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 48 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 6.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142839 / Symmetry type: POINT

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