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- EMDB-78723: Local refinement of agonist/PAM bound mGluR8 chain A LBD and CRD ... -

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Entry
Database: EMDB / ID: EMD-78723
TitleLocal refinement of agonist/PAM bound mGluR8 chain A LBD and CRD when in complex with beta-arrestin-1
Map dataLocal refinement of mGluR8 CRD and LBD when in complex with beta-arrestin-1
Sample
  • Complex: Metabotropic Glutamate Receptor 8 dimer
    • Protein or peptide: Metabotropic glutamate receptor 8
KeywordsGPCR / metabotropic glutamate receptor / membrane protein / synaptic protein / signaling protein
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsMarx DC / Levitz JT
Funding support United States, 3 items
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 19, 2026-
Header (metadata) releaseSep 23, 2026-
Map releaseSep 23, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_78723.png

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Map

FileDownload / File: emd_78723.map.gz / Format: CCP4 / Size: 1000 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement of mGluR8 CRD and LBD when in complex with beta-arrestin-1
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 640 pix.
= 528. Å		0.83 Å/pix.
x 640 pix.
= 528. Å		0.83 Å/pix.
x 640 pix.
= 528. Å

Surface

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Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.318
Minimum - Maximum-0.41371313 - 1.0686413
Average (Standard dev.)-0.00081405666 (±0.016613346)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions640640640
Spacing640640640
CellA=B=C: 528.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_78723_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #2

Fileemd_78723_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Metabotropic Glutamate Receptor 8 dimer

EntireName: Metabotropic Glutamate Receptor 8 dimer
Components
  • Complex: Metabotropic Glutamate Receptor 8 dimer
    • Protein or peptide: Metabotropic glutamate receptor 8

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Supramolecule #1: Metabotropic Glutamate Receptor 8 dimer

SupramoleculeName: Metabotropic Glutamate Receptor 8 dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 260 KDa

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Macromolecule #1: Metabotropic glutamate receptor 8

MacromoleculeName: Metabotropic glutamate receptor 8 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 101.858414 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVCEGKRSAS CPCFFLLTAK FYWILTMMQR THSQEYAHSI RVDGDIILGG LFPVHAKGER GVPCGELKKE KGIHRLEAML YAIDQINKD PDLLSNITLG VRILDTCSRD TYALEQSLTF VQALIEKDAS DVKCANGDPP IFTKPDKISG VIGAAASSVS I MVANILRL ...String:
MVCEGKRSAS CPCFFLLTAK FYWILTMMQR THSQEYAHSI RVDGDIILGG LFPVHAKGER GVPCGELKKE KGIHRLEAML YAIDQINKD PDLLSNITLG VRILDTCSRD TYALEQSLTF VQALIEKDAS DVKCANGDPP IFTKPDKISG VIGAAASSVS I MVANILRL FKIPQISYAS TAPELSDNTR YDFFSRVVPP DSYQAQAMVD IVTALGWNYV STLASEGNYG ESGVEAFTQI SR EIGGVCI AQSQKIPREP RPGEFEKIIK RLLETPNARA VIMFANEDDI RRILEAAKKL NQSGHFLWIG SDSWGSKIAP VYQ QEEIAE GAVTILPKRA SIDGFDRYFR SRTLANNRRN VWFAEFWEEN FGCKLGSHGK RNSHIKKCTG LERIARDSSY EQEG KVQFV IDAVYSMAYA LHNMHKDLCP GYIGLCPRMS TIDGKELLGY IRAVNFNGSA GTPVTFNENG DAPGRYDIFQ YQITN KSTE YKVIGHWTNQ LHLKVEDMQW AHREHTHPAS VCSLPCKPGE RKKTVKGVPC CWHCERCEGY NYQVDELSCE LCPLDQ RPN MNRTGCQLIP IIKLEWHSPW AVVPVFVAIL GIIATTFVIV TFVRYNDTPI VRASGRELSY VLLTGIFLCY SITFLMI AA PDTIICSFRR VFLGLGMCFS YAALLTKTNR IHRIFEQGKK SVTAPKFISP ASQLVITFSL ISVQLLGVFV WFVVDPPH I IIDYGEQRTL DPEKARGVLK CDISDLSLIC SLGYSILLMV TCTVYAIKTR GVPETFNEAK PIGFTMYTTC IIWLAFIPI FFGTAQSAEK MYIQTTTLTV SMSLSASVSL GMLYMPKVYI IIFHPEQNVQ KRKRSFKAVV TAATMQSKLI QKGNDRPNGE VKSELCESL ETNTSSTKTT YISYSNHSI

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
Detailssample was coexpressed with truncated beta-arrestin-1 and grk2-caax

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

49154

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5.3) / Number images used: 189406
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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