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- EMDB-31238: Cryo-EM structure of inactive mGlu2-7 heterodimer -

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Basic information

Entry
Database: EMDB / ID: EMD-31238
TitleCryo-EM structure of inactive mGlu2-7 heterodimer
Map data
Sample
  • Complex: Inactive mGlu2-7 heterodimer
    • Protein or peptide: Metabotropic glutamate receptor 2,Peptidylprolyl isomerase
    • Protein or peptide: Isoform 3 of Metabotropic glutamate receptor 7
Function / homology
Function and homology information


regulation of response to drug / group II metabotropic glutamate receptor activity / behavioral response to nicotine / G protein-coupled glutamate receptor signaling pathway / intracellular glutamate homeostasis / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / negative regulation of adenylate cyclase activity / glutamate secretion / glutamate receptor activity ...regulation of response to drug / group II metabotropic glutamate receptor activity / behavioral response to nicotine / G protein-coupled glutamate receptor signaling pathway / intracellular glutamate homeostasis / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / negative regulation of adenylate cyclase activity / glutamate secretion / glutamate receptor activity / regulation of glutamate secretion / long-term synaptic depression / regulation of dopamine secretion / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / presynaptic modulation of chemical synaptic transmission / response to cocaine / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / G protein-coupled receptor activity / gene expression / presynaptic membrane / G alpha (i) signalling events / chemical synaptic transmission / scaffold protein binding / 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 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 / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 ...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 / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein coupled receptors family 3 profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Peptidyl-prolyl cis-trans isomerase domain superfamily / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Peptidylprolyl isomerase / Metabotropic glutamate receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsDu J / Wang D / Fan H / Tai L / Lin S / Han S / Sun F / Wu B / Zhao Q
Funding support China, 4 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
National Science Foundation (NSF, China)31830020 China
National Science Foundation (NSF, China)81720108031 China
CitationJournal: Nature / Year: 2021
Title: Structures of human mGlu2 and mGlu7 homo- and heterodimers.
Authors: Juan Du / Dejian Wang / Hongcheng Fan / Chanjuan Xu / Linhua Tai / Shuling Lin / Shuo Han / Qiuxiang Tan / Xinwei Wang / Tuo Xu / Hui Zhang / Xiaojing Chu / Cuiying Yi / Peng Liu / Xiaomei ...Authors: Juan Du / Dejian Wang / Hongcheng Fan / Chanjuan Xu / Linhua Tai / Shuling Lin / Shuo Han / Qiuxiang Tan / Xinwei Wang / Tuo Xu / Hui Zhang / Xiaojing Chu / Cuiying Yi / Peng Liu / Xiaomei Wang / Yu Zhou / Jean-Philippe Pin / Philippe Rondard / Hong Liu / Jianfeng Liu / Fei Sun / Beili Wu / Qiang Zhao /
Abstract: The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system. These receptors probably exist as both ...The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties. Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.
History
DepositionApr 26, 2021-
Header (metadata) releaseJun 23, 2021-
Map releaseJun 23, 2021-
UpdateJul 7, 2021-
Current statusJul 7, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7epd
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7epd
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_31238.map.gz / Format: CCP4 / Size: 110 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.012 / Movie #1: 0.013
Minimum - Maximum-0.03784573 - 0.17691374
Average (Standard dev.)0.00036393525 (±0.0023644394)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions308308304
Spacing308308304
CellA: 321.86 Å / B: 321.86 Å / C: 317.68 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z308308304
origin x/y/z0.0000.0000.000
length x/y/z321.860321.860317.680
α/β/γ90.00090.00090.000
start NX/NY/NZ192139186
NX/NY/NZ211274246
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS308308304
D min/max/mean-0.0380.1770.000

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Supplemental data

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Sample components

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Entire : Inactive mGlu2-7 heterodimer

EntireName: Inactive mGlu2-7 heterodimer
Components
  • Complex: Inactive mGlu2-7 heterodimer
    • Protein or peptide: Metabotropic glutamate receptor 2,Peptidylprolyl isomerase
    • Protein or peptide: Isoform 3 of Metabotropic glutamate receptor 7

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Supramolecule #1: Inactive mGlu2-7 heterodimer

SupramoleculeName: Inactive mGlu2-7 heterodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: mammal environmental sample (environmental samples)

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Macromolecule #1: Metabotropic glutamate receptor 2,Peptidylprolyl isomerase

MacromoleculeName: Metabotropic glutamate receptor 2,Peptidylprolyl isomerase
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 104.904 KDa
Recombinant expressionOrganism: mammal environmental sample (environmental samples)
SequenceString: DYKDDDDGAP EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTH ALEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS T SAKLSDKS ...String:
DYKDDDDGAP EGPAKKVLTL EGDLVLGGLF PVHQKGGPAE DCGPVNEHRG IQRLEAMLFA LDRINRDPHL LPGVRLGAHI LDSCSKDTH ALEQALDFVR ASLSRGADGS RHICPDGSYA THGDAPTAIT GVIGGSYSDV SIQVANLLRL FQIPQISYAS T SAKLSDKS RYDYFARTVP PDFFQAKAMA EILRFFNWTY VSTVASEGDY GETGIEAFEL EARARNICVA TSEKVGRAMS RA AFEGVVR ALLQKPSARV AVLFTRSEDA RELLAASQRL NASFTWVASD GWGALESVVA GSEGAAEGAI TIELASYPIS DFA SYFQSL DPWNNSRNPW FREFWEQRFR CSFRQRDCAA HSLRAVPFEQ ESKIMFVVNA VYAMAHALHN MHRALCPNTT RLCD AMRPV NGRRLYKDFV LNVKFDAPFR PADTHNEVRF DRFGDGIGRY NIFTYLRAGS GRYRYQKVGY WAEGLTLDTS LIPWA SPSA GPLPASRCSE PCLQNEVKSV QPGEVCCWLC IPCQPYEYRL DEFTCADCGL GYWPNASLTG CFELPQEYIR WGDAWA VGP VTIACLGALA TLFVLGVFVR HNATPVVKAS GRELCYILLG GVFLCYCMTF IFIAKPSTAV CTLRRLGLGT AFSVCYS AL LTKTYRIARI FGGAREGAQR PRFISPASQV AICLALISGQ LLIVVAWLVV EAPGTGKETA PERREVVTLR CNHRDASM L GSLAYNVLLI ALCTLYAFKT RKCPENFNEA KFIGFTMYTT CIIWLAFLPI FYVTSSDYRV QTTTMCVSVS LSGSVVLGC LFAPKLYIIL FQPQKNVAAA GVQVETISPG DGRTFPKRGQ TCVVHYTGML EDGKKFDSSR DRNKPFKFML GKQEVIRGWE EGVAQMSVG QRAKLTISPD YAYGATGHPG IIPPHATLVF DVELLKLEEF LEVLFQGPHH HHHHHHHH

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Macromolecule #2: Isoform 3 of Metabotropic glutamate receptor 7

MacromoleculeName: Isoform 3 of Metabotropic glutamate receptor 7 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.243688 KDa
Recombinant expressionOrganism: mammal environmental sample (environmental samples)
SequenceString: GSWSHPQFEK GSGSWSHPQF EKGSLEVLFQ GPGAPQEMYA PHSIRIEGDV TLGGLFPVHA KGPSGVPCGD IKRENGIHRL EAMLYALDQ INSDPNLLPN VTLGARILDT CSRDTYALEQ SLTFVQALIQ KDTSDVRCTN GEPPVFVKPE KVVGVIGASG S SVSIMVAN ...String:
GSWSHPQFEK GSGSWSHPQF EKGSLEVLFQ GPGAPQEMYA PHSIRIEGDV TLGGLFPVHA KGPSGVPCGD IKRENGIHRL EAMLYALDQ INSDPNLLPN VTLGARILDT CSRDTYALEQ SLTFVQALIQ KDTSDVRCTN GEPPVFVKPE KVVGVIGASG S SVSIMVAN ILRLFQIPQI SYASTAPELS DDRRYDFFSR VVPPDSFQAQ AMVDIVKALG WNYVSTLASE GSYGEKGVES FT QISKEAG GLCIAQSVRI PQERKDRTID FDRIIKQLLD TPNSRAVVIF ANDEDIKQIL AAAKRADQVG HFLWVGSDSW GSK INPLHQ HEDIAEGAIT IQPKRATVEG FDAYFTSRTL ENNRRNVWFA EYWEENFNCK LTISGSKKED TDRKCTGQER IGKD SNYEQ EGKVQFVIDA VYAMAHALHH MNKDLCADYR GVCPEMEQAG GKKLLKYIRN VNFNGSAGTP VMFNKNGDAP GRYDI FQYQ TTNTSNPGYR LIGQWTDELQ LNIEDMQWGK GVREIPASVC TLPCKPGQRK KTQKGTPCCW TCEPCDGYQY QFDEMT CQH CPYDQRPNEN RTGCQDIPII KLEWHSPWAV IPVFLAMLGI IATIFVMATF IRYNDTPIVR ASGRELSYVL LTGIFLC YI ITFLMIAKPD VAVCSFRRVF LGLGMCISYA ALLTKTNRIY RIFEQGKKSV TAPRLISPTS QLAITSSLIS VQLLGVFI W FIVDPPNIII DYDEHKTMNP EQARGVLKCD ITDLQIICSL GYSILLMVTC TVYAFKTRGV PENFNEAKYI GFTMYTTCI VWLAFIPIFF GTAQSAEKLY IQTTTLTISM NLSASVALGM LYMPKVYIII FHPELNVQKR AAAAILWHEM WHEGLEEASR LYFGERNVK GMFEVLEPLH AMMERGPQTL KETSFNQAYG RDLMEAQEWC RKYMKSGNVK DLTQAWDLYY HVFRRISKQE F DYKDDDD

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 2.1875 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1113538

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