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- EMDB-37506: mGlu2-mGlu4 heterodimer bound mGlu4 agonist E7P -

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Basic information

Entry
Database: EMDB / ID: EMD-37506
TitlemGlu2-mGlu4 heterodimer bound mGlu4 agonist E7P
Map data
Sample
  • Complex: mGlu2-mGlu4 heterodimer bound L-AP4
    • Protein or peptide: Metabotropic glutamate receptor 4
    • Protein or peptide: Metabotropic glutamate receptor 2
  • Ligand: (2S)-2-amino-4-phosphonobutanoic acid
KeywordsGPCR / MEMBRANE PROTEIN
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 / neurotransmitter secretion / G protein-coupled glutamate receptor signaling pathway / negative regulation of adenylate cyclase activity / astrocyte projection ...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 / neurotransmitter secretion / G protein-coupled glutamate receptor signaling pathway / negative regulation of adenylate cyclase activity / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / glutamate secretion / long-term synaptic depression / regulation of glutamate secretion / cellular response to stress / regulation of dopamine secretion / regulation of synaptic transmission, glutamatergic / regulation of neuron apoptotic process / calcium channel regulator activity / presynaptic modulation of chemical synaptic transmission / response to cocaine / G protein-coupled receptor activity / Sensory perception of sweet, bitter, and umami (glutamate) taste / presynapse / presynaptic membrane / cytoplasmic vesicle / scaffold protein binding / G alpha (i) signalling events / gene expression / chemical synaptic transmission / postsynaptic membrane / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / axon / dendrite / glutamatergic synapse / plasma membrane
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 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / G-protein coupled receptors family 3 signature 3. ...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 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / G-protein coupled receptors family 3 signature 3. / 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 2 / Metabotropic glutamate receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.46 Å
AuthorsZhang Y / Liu J
Funding support China, 1 items
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, 2023-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37506.png

Downloads & links

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Map

FileDownload / File: emd_37506.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 416 pix.
= 386.88 Å		0.93 Å/pix.
x 416 pix.
= 386.88 Å		0.93 Å/pix.
x 416 pix.
= 386.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.209
Minimum - Maximum-0.7462208 - 1.949532
Average (Standard dev.)0.0071454747 (±0.033173174)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 386.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : mGlu2-mGlu4 heterodimer bound L-AP4

EntireName: mGlu2-mGlu4 heterodimer bound L-AP4
Components
  • Complex: mGlu2-mGlu4 heterodimer bound L-AP4
    • Protein or peptide: Metabotropic glutamate receptor 4
    • Protein or peptide: Metabotropic glutamate receptor 2
  • Ligand: (2S)-2-amino-4-phosphonobutanoic acid

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Supramolecule #1: mGlu2-mGlu4 heterodimer bound L-AP4

SupramoleculeName: mGlu2-mGlu4 heterodimer bound L-AP4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Metabotropic glutamate receptor 4

MacromoleculeName: Metabotropic glutamate receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.36532 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINND PDLLPNITLG ARILDTCSRD THALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV SIMVANILRL FKIPQISYAS TAPDLSDNSR Y DFFSRVVP ...String:
KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINND PDLLPNITLG ARILDTCSRD THALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV SIMVANILRL FKIPQISYAS TAPDLSDNSR Y DFFSRVVP SDTYQAQAMV DIVRALKWNY VSTVASEGSY GESGVEAFIQ KSREDGGVCI AQSVKIPREP KAGEFDKIIR RL LETSNAR AVIIFANEDD IRRVLEAARR ANQTGHFFWM GSDSWGSKIA PVLHLEEVAE GAVTILPKRM SVRGFDRYFS SRT LDNNRR NIWFAEFWED NFHCKLSRHA LKKGSHVKKC TNRERIGQDS AYEQEGKVQF VIDAVYAMGH ALHAMHRDLC PGRV GLCPR MDPVDGTQLL KYIRNVNFSG IAGNPVTFNE NGDAPGRYDI YQYQLRNDSA EYKVIGSWTD HLHLRIERMH WPGSG QQLP RSICSLPCQP GERKKTVKGM PCCWHCEPCT GYQYQVDRYT CKTCPYDMRP TENRTGCRPI PIIKLEWGSP WAVLPL FLA VVGIAATLFV VITFVRYNDT PIVKASGREL SYVLLAGIFL CYATTFLMIA EPDLGTCSLR RIFLGLGMSI SYAALLT KT NRIYRIFEQG KRSVSAPRFI SPASQLAITF SLISLQLLGI CVWFVVDPSH SVVDFQDQRT LDPRFARGVL KCDISDLS L ICLLGYSMLL MVTCTVYAIK TRGVPETFNE AKPIGFTMYT TCIVWLAFIP IFFGTSQSAD KLYIQTTTLT VSVSLSASV SLGMLYMPKV YIILFHPEQN VPKRKRSLKA VVTAATMSNK FTQKGNFRPN GEAKSELCEN LEAPALATKQ TYVTYTNHAI

UniProtKB: Metabotropic glutamate receptor 4

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Macromolecule #2: Metabotropic glutamate receptor 2

MacromoleculeName: Metabotropic glutamate receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.861367 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTHA LEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS TSAKLSDKSR Y DYFARTVP ...String:
EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTHA LEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS TSAKLSDKSR Y DYFARTVP PDFFQAKAMA EILRFFNWTY VSTVASEGDY GETGIEAFEL EARARNICVA TSEKVGRAMS RAAFEGVVRA LL QKPSARV AVLFTRSEDA RELLAASQRL NASFTWVASD GWGALESVVA GSEGAAEGAI TIELASYPIS DFASYFQSLD PWN NSRNPW FREFWEQRFR CSFRQRDCAA HSLRAVPFEQ ESKIMFVVNA VYAMAHALHN MHRALCPNTT RLCDAMRPVN GRRL YKDFV LNVKFDAPFR PADTHNEVRF DRFGDGIGRY NIFTYLRAGS GRYRYQKVGY WAEGLTLDTS LIPWASPSAG PLPAS RCSE PCLQNEVKSV QPGEVCCWLC IPCQPYEYRL DEFTCADCGL GYWPNASLTG CFELPQEYIR WGDAWAVGPV TIACLG ALA TLFVLGVFVR HNATPVVKAS GRELCYILLG GVFLCYCMTF IFIAKPSTAV CTLRRLGLGT AFSVCYSALL TKTNRIA RI FGGAREGAQR PRFISPASQV AICLALISGQ LLIVVAWLVV EAPGTGKETA PERREVVTLR CNHRDASMLG SLAYNVLL I ALCTLYAFKT RKCPENFNEA KFIGFTMYTT CIIWLAFLPI FYVTSSDYRV QTTTMCVSVS LSGSVVLGCL FAPKLHIIL FQPQKNVVSH RAPTSRFGSA AARASSSLGQ GSGSQFVPTV CNGREVVDST TSSL

UniProtKB: Metabotropic glutamate receptor 2

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Macromolecule #3: (2S)-2-amino-4-phosphonobutanoic acid

MacromoleculeName: (2S)-2-amino-4-phosphonobutanoic acid / type: ligand / ID: 3 / Number of copies: 1 / Formula: E7P
Molecular weightTheoretical: 183.1 Da
Chemical component information

ChemComp-E7P:
(2S)-2-amino-4-phosphonobutanoic acid / agonist*YM

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 112924
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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