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- EMDB-78696: Local Refinement of G protein heterotrimer bound to scFv14 when i... -

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Entry
Database: EMDB / ID: EMD-78696
TitleLocal Refinement of G protein heterotrimer bound to scFv14 when in complex with active mGluR8
Map dataLocal refinement of G protein heterotrimer bound to scFv14 when in complex with mGluR8
Sample
  • Complex: Metabotropic Glutamate receptor bound to G proteins alpha i-1, beta-1, and gamma-2 in the presence of agonist and PAM and scFv14
    • Complex: G protein heterotrimer bound to scFv14
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: scFv-14
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Complex: mGluR8 homodimer bound to agonist and PAM
      • Protein or peptide: Metabotropic glutamate receptor 8
KeywordsGPCR / metabotropic glutamate receptor / membrane protein / synaptic protein / signaling protein
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.9 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 18, 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_78696.png

Downloads & links

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Map

FileDownload / File: emd_78696.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationLocal refinement of G protein heterotrimer bound to scFv14 when in complex with mGluR8
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 512 pix.
= 593.92 Å		1.16 Å/pix.
x 512 pix.
= 593.92 Å		1.16 Å/pix.
x 512 pix.
= 593.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.16 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.221
Minimum - Maximum-0.29441568 - 0.9139233
Average (Standard dev.)-0.0003007433 (±0.0111224335)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 593.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_78696_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_78696_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Metabotropic Glutamate receptor bound to G proteins alpha i-1, be...

EntireName: Metabotropic Glutamate receptor bound to G proteins alpha i-1, beta-1, and gamma-2 in the presence of agonist and PAM and scFv14
Components
  • Complex: Metabotropic Glutamate receptor bound to G proteins alpha i-1, beta-1, and gamma-2 in the presence of agonist and PAM and scFv14
    • Complex: G protein heterotrimer bound to scFv14
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: scFv-14
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Complex: mGluR8 homodimer bound to agonist and PAM
      • Protein or peptide: Metabotropic glutamate receptor 8

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Supramolecule #1: Metabotropic Glutamate receptor bound to G proteins alpha i-1, be...

SupramoleculeName: Metabotropic Glutamate receptor bound to G proteins alpha i-1, beta-1, and gamma-2 in the presence of agonist and PAM and scFv14
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 188 KDa

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Supramolecule #2: G protein heterotrimer bound to scFv14

SupramoleculeName: G protein heterotrimer bound to scFv14 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: mGluR8 homodimer bound to agonist and PAM

SupramoleculeName: mGluR8 homodimer bound to agonist and PAM / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 94.195492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAAAQEYA HSIRVDGDII LGGLFPVHAK GERGVPCGEL KKEKGIHRLE AMLYAIDQIN KDPDLLSNI TLGVRILDTC SRDTYALEQS LTFVQALIEK DASDVKCANG DPPIFTKPDK ISGVIGAAAS SVSIMVANIL R LFKIPQIS ...String:
MKTIIALSYI FCLVFADYKD DDDAAAQEYA HSIRVDGDII LGGLFPVHAK GERGVPCGEL KKEKGIHRLE AMLYAIDQIN KDPDLLSNI TLGVRILDTC SRDTYALEQS LTFVQALIEK DASDVKCANG DPPIFTKPDK ISGVIGAAAS SVSIMVANIL R LFKIPQIS YASTAPELSD NTRYDFFSRV VPPDSYQAQA MVDIVTALGW NYVSTLASEG NYGESGVEAF TQISREIGGV CI AQSQKIP REPRPGEFEK IIKRLLETPN ARAVIMFANE DDIRRILEAA KKLNQSGHFL WIGSDSWGSK IAPVYQQEEI AEG AVTILP KRASIDGFDR YFRSRTLANN RRNVWFAEFW EENFGCKLGS HGKRNSHIKK CTGLERIARD SSYEQEGKVQ FVID AVYSM AYALHNMHKD LCPGYIGLCP RMSTIDGKEL LGYIRAVNFN GSAGTPVTFN ENGDAPGRYD IFQYQITNKS TEYKV IGHW TNQLHLKVED MQWAHREHTH PASVCSLPCK PGERKKTVKG VPCCWHCERC EGYNYQVDEL SCELCPLDQR PNMNRT GCQ LIPIIKLEWH SPWAVVPVFV AILGIIATTF VIVTFVRYND TPIVRASGRE LSYVLLTGIF LCYSITFLMI AAPDTII CS FRRVFLGLGM CFSYAALLTK TNRIHRIFEQ GKKSVTAPKF ISPASQLVIT FSLISVQLLG VFVWFVVDPP HIIIDYGE Q RTLDPEKARG VLKCDISDLS LICSLGYSIL LMVTCTVYAI KTRGVPETFN EAKPIGFTMY TTCIIWLAFI PIFFGTAQS AEKMYIQTTT LTVSMSLSAS VSLGMLYMPK VYIIIFHPEQ N

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #3: scFv-14

MacromoleculeName: scFv-14 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 27.784896 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAAHHHHHH HH

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Macromolecule #4: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.415031 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.286891 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HHHHHHLEVL FQGPGSSGSE LDQLRQEAEQ LKNQIRDARK ACADATLSQI TNNIDPVGRI QMRTRRTLRG HLAKIYAMHW GTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVMT CAYAPSGNYV ACGGLDNICS IYNLKTREGN VRVSRELAGH T GYLSCCRF ...String:
HHHHHHLEVL FQGPGSSGSE LDQLRQEAEQ LKNQIRDARK ACADATLSQI TNNIDPVGRI QMRTRRTLRG HLAKIYAMHW GTDSRLLVS ASQDGKLIIW DSYTTNKVHA IPLRSSWVMT CAYAPSGNYV ACGGLDNICS IYNLKTREGN VRVSRELAGH T GYLSCCRF LDDNQIVTSS GDTTCALWDI ETGQQTTTFT GHTGDVMSLS LAPDTRLFVS GACDASAKLW DVREGMCRQT FT GHESDIN AICFFPNGNA FATGSDDATC RLFDLRADQE LMTYSHDNII CGITSVSFSK SGRLLLAGYD DFNCNVWDAL KAD RAGVLA GHDNRVSCLG VTDDGMAVAT GSWDSFLKIW N

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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
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 48.0 e/Å2
Electron beamAcceleration voltage: 200 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

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Image processing

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

23996

Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 142834
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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