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- PDB-9mb9: Cryo-EM structure of Gi-bound GPCR -

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Basic information

Entry
Database: PDB / ID: 9mb9
TitleCryo-EM structure of Gi-bound GPCR
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Metabotropic glutamate receptor 8
KeywordsMEMBRANE PROTEIN / Complex / PROTEIN / Antagonist / MEMBRANE / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
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 / adenylate cyclase inhibitor activity / regulation of synaptic transmission, glutamatergic / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway ...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 / adenylate cyclase inhibitor activity / regulation of synaptic transmission, glutamatergic / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / visual perception / cellular response to forskolin / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / 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 / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / GTP binding / protein-containing complex binding / nucleolus / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / 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 / G-protein alpha subunit, group I / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / 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
: / Chem-HVG / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsZhao, J. / Zhao, C. / Sun, H. / Shao, Z.H.
Funding support1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)290,4058
Polymers289,5665
Non-polymers8393
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 2 molecules DR

#1: Protein Metabotropic glutamate receptor 8 / mGluR8


Mass: 101858.414 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: O00222

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

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37573.988 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Non-polymers , 2 types, 3 molecules

#5: Chemical ChemComp-HVG / 4-[(S)-amino(carboxy)methyl]benzene-1,2-dicarboxylic acid / (S)-3,4-Dicarboxyphenylglycine (DCPG)


Mass: 239.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H9NO6 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-A1ENS / ~{N}-[3-chloranyl-4-(5-chloranylpyridin-2-yl)oxy-phenyl]pyridine-2-carboxamide


Mass: 360.194 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H11Cl2N3O2 / 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

ComponentName: GPCR bound to Gi1 heterotrimer / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1300 nm / Nominal defocus min: 500 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
8PHENIXmodel refinement
13Coot3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 290681 / Symmetry type: POINT
RefinementHighest resolution: 2.97 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00417323
ELECTRON MICROSCOPYf_angle_d0.61523487
ELECTRON MICROSCOPYf_dihedral_angle_d5.122354
ELECTRON MICROSCOPYf_chiral_restr0.0462659
ELECTRON MICROSCOPYf_plane_restr0.0052994

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