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- PDB-8wgb: mGlu2-4 heterodimer bound with Gi -

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Basic information

Entry
Database: PDB / ID: 8wgb
TitlemGlu2-4 heterodimer bound with Gi
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • (Metabotropic glutamate receptor ...) x 2
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / regulation of response to drug / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / intracellular glutamate homeostasis / behavioral response to nicotine / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / neurotransmitter secretion / Class C/3 (Metabotropic glutamate/pheromone receptors) ...adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / regulation of response to drug / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / intracellular glutamate homeostasis / behavioral response to nicotine / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / neurotransmitter secretion / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / long-term synaptic depression / glutamate secretion / GTP metabolic process / regulation of glutamate secretion / astrocyte projection / cellular response to stress / regulation of dopamine secretion / positive regulation of macroautophagy / regulation of synaptic transmission, glutamatergic / regulation of neuron apoptotic process / Adenylate cyclase inhibitory pathway / presynaptic modulation of chemical synaptic transmission / response to cocaine / calcium channel regulator activity / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / GDP binding / Vasopressin regulates renal water homeostasis via Aquaporins / 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 / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / presynapse / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / presynaptic membrane / GTPase binding / Ca2+ pathway / cytoplasmic vesicle / scaffold protein binding / fibroblast proliferation / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / gene expression / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / ciliary basal body / G protein-coupled receptor signaling pathway / axon / lysosomal membrane / cell division / GTPase activity / synapse / dendrite
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor 2 / 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, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor 2 / 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
GLUTAMIC ACID / : / Guanine nucleotide-binding protein G(i) subunit alpha-3 / 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 / Metabotropic glutamate receptor 2 / Metabotropic glutamate receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsZhang, Y. / Liu, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of orientated asymmetry in a mGlu heterodimer.
Authors: Weizhu Huang / Nan Jin / Jia Guo / Cangsong Shen / Chanjuan Xu / Kun Xi / Léo Bonhomme / Robert B Quast / Dan-Dan Shen / Jiao Qin / Yi-Ru Liu / Yuxuan Song / Yang Gao / Emmanuel Margeat / ...Authors: Weizhu Huang / Nan Jin / Jia Guo / Cangsong Shen / Chanjuan Xu / Kun Xi / Léo Bonhomme / Robert B Quast / Dan-Dan Shen / Jiao Qin / Yi-Ru Liu / Yuxuan Song / Yang Gao / Emmanuel Margeat / Philippe Rondard / Jean-Philippe Pin / Yan Zhang / Jianfeng Liu /
Abstract: The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric ...The structural basis for the allosteric interactions within G protein-coupled receptors (GPCRs) heterodimers remains largely unknown. The metabotropic glutamate (mGlu) receptors are complex dimeric GPCRs important for the fine tuning of many synapses. Heterodimeric mGlu receptors with specific allosteric properties have been identified in the brain. Here we report four cryo-electron microscopy structures of mGlu2-4 heterodimer in different states: an inactive state bound to antagonists, two intermediate states bound to either mGlu2 or mGlu4 agonist only and an active state bound to both glutamate and a mGlu4 positive allosteric modulator (PAM) in complex with Gi protein. In addition to revealing a unique PAM binding pocket among mGlu receptors, our data bring important information for the asymmetric activation of mGlu heterodimers. First, we show that agonist binding to a single subunit in the extracellular domain is not sufficient to stabilize an active dimer conformation. Single-molecule FRET data show that the monoliganded mGlu2-4 can be found in both intermediate states and an active one. Second, we provide a detailed view of the asymmetric interface in seven-transmembrane (7TM) domains and identified key residues within the mGlu2 7TM that limits its activation leaving mGlu4 as the only subunit activating G proteins.
History
DepositionSep 20, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Dec 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.3May 28, 2025Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
B: Metabotropic glutamate receptor 2
C: Guanine nucleotide-binding protein G(i) subunit alpha-3
R: Metabotropic glutamate receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)278,5688
Polymers277,9585
Non-polymers6103
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 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
#2: 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
#4: Protein Guanine nucleotide-binding protein G(i) subunit alpha-3


Mass: 40584.156 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08754

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Metabotropic glutamate receptor ... , 2 types, 2 molecules BR

#3: Protein Metabotropic glutamate receptor 2


Mass: 93861.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14416
#5: Protein Metabotropic glutamate receptor 4


Mass: 98365.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q14833

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Non-polymers , 2 types, 3 molecules

#6: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H9NO4
#7: Chemical ChemComp-W9R / (1R,2S)-2-[[3,5-bis(chloranyl)phenyl]carbamoyl]cyclohexane-1-carboxylic acid


Mass: 316.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15Cl2NO3 / 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: mGlu2-mGlu4 heterodimer bound Gi / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: 3000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 157293 / Symmetry type: POINT

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