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- PDB-7e9h: Cryo-EM structure of Gi-bound metabotropic glutamate receptor mGlu4 -

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Basic information

Entry
Database: PDB / ID: 7e9h
TitleCryo-EM structure of Gi-bound metabotropic glutamate receptor mGlu4
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Metabotropic glutamate receptor 4
  • scFv16
KeywordsMEMBRANE PROTEIN / mGlu4 / GPCR / Cryo-EM / complex
Function / homology
Function and homology information


adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / 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 / GTP metabolic process / G protein-coupled dopamine receptor signaling pathway / positive regulation of macroautophagy ...adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / 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 / GTP metabolic process / G protein-coupled dopamine receptor signaling pathway / positive regulation of macroautophagy / Adenylate cyclase inhibitory pathway / regulation of neuron apoptotic process / regulation of synaptic transmission, glutamatergic / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / presynapse / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / midbody / G alpha (i) signalling events / fibroblast proliferation / cytoplasmic vesicle / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / cell population proliferation / Ras protein signal transduction / positive regulation of MAPK cascade / Extra-nuclear estrogen signaling / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / protein-containing complex binding / nucleolus / GTP binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor / G-protein coupled receptors family 3 signature 1. / 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 / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 ...GPCR, family 3, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor / G-protein coupled receptors family 3 signature 1. / 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 / G-protein coupled receptors family 3 signature 3. / 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 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / Periplasmic binding protein-like I / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / 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
PHOSPHOSERINE / 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 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsLin, S. / Han, S. / Zhao, Q. / Wu, B.
Funding support China, 5items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
National Science Foundation (NSF, China)81872915 China
National Science Foundation (NSF, China)81773792 China
National Science Foundation (NSF, China)81973373 China
CitationJournal: Nature / Year: 2021
Title: Structures of G-bound metabotropic glutamate receptors mGlu2 and mGlu4.
Authors: Shuling Lin / Shuo Han / Xiaoqing Cai / Qiuxiang Tan / Kexiu Zhou / Dejian Wang / Xinwei Wang / Juan Du / Cuiying Yi / Xiaojing Chu / Antao Dai / Yan Zhou / Yan Chen / Yu Zhou / Hong Liu / ...Authors: Shuling Lin / Shuo Han / Xiaoqing Cai / Qiuxiang Tan / Kexiu Zhou / Dejian Wang / Xinwei Wang / Juan Du / Cuiying Yi / Xiaojing Chu / Antao Dai / Yan Zhou / Yan Chen / Yu Zhou / Hong Liu / Jianfeng Liu / Dehua Yang / Ming-Wei Wang / Qiang Zhao / Beili Wu /
Abstract: The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central ...The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system). It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation. However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu-G structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs.
History
DepositionMar 4, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
R: Metabotropic glutamate receptor 4
S: Metabotropic glutamate receptor 4
A: Guanine nucleotide-binding protein G(i) subunit alpha-3
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
D: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)313,8548
Polymers313,4846
Non-polymers3702
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9190 Å2
ΔGint-61 kcal/mol
Surface area104960 Å2

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Components

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

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


Mass: 40552.070 Da / Num. of mol.: 1 / Mutation: S47N, F191D, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P08754
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Baculovirus expression vector pFastBac1-HM / 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: Baculovirus expression vector pFastBac1-HM / References: UniProt: P59768

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Protein / Antibody / Non-polymers , 3 types, 5 molecules RSD

#1: Protein Metabotropic glutamate receptor 4 / mGluR4


Mass: 99458.359 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM4, GPRC1D, MGLUR4 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q14833
#5: Antibody scFv16


Mass: 27409.588 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Baculovirus expression vector pFastBac1-HM
#6: Chemical ChemComp-SEP / PHOSPHOSERINE / PHOSPHONOSERINE


Type: L-peptide linking / Mass: 185.072 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8NO6P / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Complex of mGlu4 homodimer with heterotrimeric Gi3 protein in presence of antibody
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 7.4
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.1_4122refinement
PHENIX1.19.1_4122refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 617760 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 65.37 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001717194
ELECTRON MICROSCOPYf_angle_d0.462323449
ELECTRON MICROSCOPYf_chiral_restr0.03892736
ELECTRON MICROSCOPYf_plane_restr0.00313021
ELECTRON MICROSCOPYf_dihedral_angle_d21.41995823

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