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- EMDB-63772: Cryo-EM structure of antagonist-bound GPCR -

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Basic information

Entry
Database: EMDB / ID: EMD-63772
TitleCryo-EM structure of antagonist-bound GPCR
Map data
Sample
  • Complex: GPCR bound to an antagonist
    • Protein or peptide: Metabotropic glutamate receptor 8
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
KeywordsMembrane protein / Antagonist
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 / regulation of synaptic transmission, glutamatergic / visual perception / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G alpha (i) signalling events / plasma membrane
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 / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Metabotropic glutamate receptor 8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 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_63772.png

Downloads & links

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Map

FileDownload / File: emd_63772.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.5 Å/pix.
x 240 pix.
= 360. Å		1.5 Å/pix.
x 240 pix.
= 360. Å		1.5 Å/pix.
x 240 pix.
= 360. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.5 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.47731337 - 1.0803323
Average (Standard dev.)-0.0010904507 (±0.023383)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
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 VFT and CRD domains

Fileemd_63772_additional_1.map
AnnotationLocal refinement focused on mGluR8 VFT and CRD domains
Projections & Slices
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Half map: #2

Fileemd_63772_half_map_1.map
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Half map: #1

Fileemd_63772_half_map_2.map
Projections & Slices
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Sample components

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Entire : GPCR bound to an antagonist

EntireName: GPCR bound to an antagonist
Components
  • Complex: GPCR bound to an antagonist
    • Protein or peptide: Metabotropic glutamate receptor 8
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

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Supramolecule #1: GPCR bound to an antagonist

SupramoleculeName: GPCR bound to an antagonist / type: complex / ID: 1 / Parent: 0 / 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: 101.858414 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 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

UniProtKB: Metabotropic glutamate receptor 8

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Macromolecule #2: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

MacromoleculeName: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
type: ligand / ID: 2 / Number of copies: 2 / Formula: Z99
Molecular weightTheoretical: 353.369 Da
Chemical component information

ChemComp-Z99:
2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

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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: 1.2 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: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: Coot / Number images used: 121664
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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