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- EMDB-63771: Cryo-EM structure of complex of transducer-bound GPCR -

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Basic information

Entry
Database: EMDB / ID: EMD-63771
TitleCryo-EM structure of complex of transducer-bound GPCR
Map data
Sample
  • Complex: mGluR8 bound to beta-arrestin 1
    • Complex: Transducer-bound GPCR
      • Protein or peptide: Beta-arrestin-1
    • Complex: scFv
      • Protein or peptide: scFv
    • Protein or peptide: Metabotropic glutamate receptor 8
  • Ligand: GLUTAMIC ACID
KeywordsMembrane protein / Complex / Arrestin / Singaling protein
Function / homology
Function and homology information


group III metabotropic glutamate receptor activity / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / angiotensin receptor binding / TGFBR3 regulates TGF-beta signaling / Activation of SMO / negative regulation of interleukin-8 production / G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor internalization / arrestin family protein binding / Class C/3 (Metabotropic glutamate/pheromone receptors) ...group III metabotropic glutamate receptor activity / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / angiotensin receptor binding / TGFBR3 regulates TGF-beta signaling / Activation of SMO / negative regulation of interleukin-8 production / G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor internalization / arrestin family protein binding / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / Lysosome Vesicle Biogenesis / negative regulation of NF-kappaB transcription factor activity / positive regulation of cardiac muscle hypertrophy / Golgi Associated Vesicle Biogenesis / stress fiber assembly / positive regulation of Rho protein signal transduction / pseudopodium / negative regulation of interleukin-6 production / positive regulation of receptor internalization / negative regulation of Notch signaling pathway / enzyme inhibitor activity / regulation of synaptic transmission, glutamatergic / Activated NOTCH1 Transmits Signal to the Nucleus / insulin-like growth factor receptor binding / clathrin-coated pit / negative regulation of protein ubiquitination / visual perception / GTPase activator activity / cytoplasmic vesicle membrane / Signaling by high-kinase activity BRAF mutants / G protein-coupled receptor binding / G protein-coupled receptor activity / MAP2K and MAPK activation / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / endocytic vesicle membrane / positive regulation of protein phosphorylation / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Cargo recognition for clathrin-mediated endocytosis / Signaling by BRAF and RAF1 fusions / Clathrin-mediated endocytosis / protein transport / Thrombin signalling through proteinase activated receptors (PARs) / cytoplasmic vesicle / ubiquitin-dependent protein catabolic process / G alpha (i) signalling events / G alpha (s) signalling events / molecular adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / transcription coactivator activity / positive regulation of ERK1 and ERK2 cascade / Ub-specific processing proteases / protein ubiquitination / nuclear body / Golgi membrane / lysosomal membrane / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / chromatin / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 8 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain ...GPCR, family 3, metabotropic glutamate receptor 8 / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / GPCR, family 3, metabotropic glutamate receptor / : / Arrestin-like, C-terminal / 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 / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Immunoglobulin E-set
Similarity search - Domain/homology
Metabotropic glutamate receptor 8 / Beta-arrestin-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsZhao J / Zhao C / Sun H / Shao ZH / Sun JP
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Cell / Year: 2025
Title: Structural characterization of five functional states of metabotropic glutamate receptor 8.
Authors: Jie Zhao / Yue Deng / Zheng Xu / Chanjuan Xu / Chang Zhao / Ziyan Li / Hui Sun / Xiaowen Tian / Yuxuan Song / Marta Cimadevila / Heli Wang / Yuxuan Liu / Xiaoyu Zhang / Yiyang Chen / Suyue ...Authors: Jie Zhao / Yue Deng / Zheng Xu / Chanjuan Xu / Chang Zhao / Ziyan Li / Hui Sun / Xiaowen Tian / Yuxuan Song / Marta Cimadevila / Heli Wang / Yuxuan Liu / Xiaoyu Zhang / Yiyang Chen / Suyue Sun / Xihao Yong / Lantian Su / Yixiao He / Yi Zhong / Hao Yang / Jean-Philippe Pin / Wei Yan / Zhenhua Shao / Jianfeng Liu /
Abstract: Metabotropic glutamate receptors (mGluRs) are dimeric class C G protein-coupled receptors, which play crucial roles in brain physiology and pathology. Among them, mGlu8 is the least characterized, ...Metabotropic glutamate receptors (mGluRs) are dimeric class C G protein-coupled receptors, which play crucial roles in brain physiology and pathology. Among them, mGlu8 is the least characterized, though it is physiologically important. While recognized to signal via G proteins, the involvement of β-arrestin is unknown. Here, we found that both mGlu8 agonists and positive allosteric modulators (PAMs) activate G signaling, but mainly agonists induce β-arrestin recruitment. We solved five human mGlu8 cryo-electron microscopy (cryo-EM) structures in various states: apo, antagonist-bound, agonist + PAM-bound, agonist + PAM-bound with G protein, and agonist-bound with β-arrestin1 states. They revealed a unique PAM-binding pocket at the extracellular side of the TM6/TM7 interface. Agonist and PAM promote active mGlu8 association with one G protein asymmetrically (2:1), while two β-arrestin1 can interact symmetrically (2:2) to both subunits of an inactive dimer state to promote constitutive internalization. These findings elucidate how mGlu8 selectively engages transducers, offering insights into its signaling capabilities and selective drug development.
History
DepositionMar 15, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63771.png

Downloads & links

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Map

FileDownload / File: emd_63771.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 480 pix.
= 360. Å		0.75 Å/pix.
x 480 pix.
= 360. Å		0.75 Å/pix.
x 480 pix.
= 360. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.75 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.055
Minimum - Maximum-0.2044817 - 0.41892272
Average (Standard dev.)0.00004281165 (±0.008559222)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 360.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local refinement focused on mGluR8 TMD

Fileemd_63771_additional_1.map
AnnotationLocal refinement focused on mGluR8 TMD
Projections & Slices
AxesZYX

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Additional map: Local refinement focused on mGluR8 VFT and CRD

Fileemd_63771_additional_2.map
AnnotationLocal refinement focused on mGluR8 VFT and CRD
Projections & Slices
AxesZYX

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Additional map: Local refinement focused on arrestin-2

Fileemd_63771_additional_3.map
AnnotationLocal refinement focused on arrestin-2
Projections & Slices
AxesZYX

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Histogram

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Additional map: Local refinement focused on arrestin-1

Fileemd_63771_additional_4.map
AnnotationLocal refinement focused on arrestin-1
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_63771_half_map_1.map
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_63771_half_map_2.map
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Sample components

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Entire : mGluR8 bound to beta-arrestin 1

EntireName: mGluR8 bound to beta-arrestin 1
Components
  • Complex: mGluR8 bound to beta-arrestin 1
    • Complex: Transducer-bound GPCR
      • Protein or peptide: Beta-arrestin-1
    • Complex: scFv
      • Protein or peptide: scFv
    • Protein or peptide: Metabotropic glutamate receptor 8
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: mGluR8 bound to beta-arrestin 1

SupramoleculeName: mGluR8 bound to beta-arrestin 1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Transducer-bound GPCR

SupramoleculeName: Transducer-bound GPCR / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: scFv

SupramoleculeName: scFv / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.233348 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI EKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD ICLFNTA QYKCPVAMEE ADDTVAPSST FCKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP ENETPVDTNL

UniProtKB: Beta-arrestin-1

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Macromolecule #2: Metabotropic glutamate receptor 8

MacromoleculeName: Metabotropic glutamate receptor 8 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.082297 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 EIGGVSI 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 ETN(TPO)S(SEP)(TPO)KTT YISYSNHSI

UniProtKB: Metabotropic glutamate receptor 8

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Macromolecule #3: scFv

MacromoleculeName: scFv / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.079879 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYKYVPVT FGCGTKVEIG TTAASGSSGG SSSGAEVQLV ESGGGLVQPG GSLRLSCAAS GFNVYSSSIH W VRQAPGKC ...String:
MGDIQMTQSP SSLSASVGDR VTITCRASQS VSSAVAWYQQ KPGKAPKLLI YSASSLYSGV PSRFSGSRSG TDFTLTISSL QPEDFATYY CQQYKYVPVT FGCGTKVEIG TTAASGSSGG SSSGAEVQLV ESGGGLVQPG GSLRLSCAAS GFNVYSSSIH W VRQAPGKC LEWVASISSY YGYTYYADSV KGRFTISADT SKNTAYLQMN SLRAEDTAVY YCARSRQFWY SGLDYWGQGT LV TVSS

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Macromolecule #4: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 4 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.3 µm / Nominal defocus min: 0.6 µm
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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot / Number images used: 205076
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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