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- EMDB-31236: Cryo-EM structure of LY354740-bound mGlu2 homodimer -

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Basic information

Entry
Database: EMDB / ID: EMD-31236
TitleCryo-EM structure of LY354740-bound mGlu2 homodimer
Map data
Sample
  • Complex: LY354740-bound mGlu2 homodimer
    • Protein or peptide: Metabotropic glutamate receptor 2
    • Protein or peptide: Anti-RON nanobody
  • Ligand: (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
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 / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / 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 / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / 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 / G protein-coupled receptor activity / presynaptic membrane / gene expression / 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. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Metabotropic glutamate receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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: 7.6
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 7.6
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7epb
  • Surface level: 7.6
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7epb
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31236.png

Downloads & links

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Map

FileDownload / File: emd_31236.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 7.6 / Movie #1: 7.6
Minimum - Maximum-4.847864 - 25.337101
Average (Standard dev.)0.19761282 (±0.7825625)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 291.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z291.200291.200291.200
α/β/γ90.00090.00090.000
start NX/NY/NZ192139186
NX/NY/NZ211274246
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-4.84825.3370.198

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Supplemental data

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Sample components

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Entire : LY354740-bound mGlu2 homodimer

EntireName: LY354740-bound mGlu2 homodimer
Components
  • Complex: LY354740-bound mGlu2 homodimer
    • Protein or peptide: Metabotropic glutamate receptor 2
    • Protein or peptide: Anti-RON nanobody
  • Ligand: (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

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Supramolecule #1: LY354740-bound mGlu2 homodimer

SupramoleculeName: LY354740-bound mGlu2 homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: mammal environmental sample (environmental samples)

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Macromolecule #1: Metabotropic glutamate receptor 2

MacromoleculeName: Metabotropic glutamate receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.061445 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 HNATPVVKAA GRELCYILLG GVFLCYCMTF IFIAKPSTAV CTLRRLGLGT AFSVCYS AL LTKTNRIARI FGGAREGAQR PRFISPASQV AICLALISGQ LLIVVAWLVV EAPGTGKETA PERREVVTLR CNHRDASM L GSLAYNVLLI ALCTLYAFKT RKCPENFNEA KFIGFTMYTT CIIWLAFLPI FYVTSSDYRV QTTTMCVSVS LSGSVVLGC LFAPKLHIIL FQPQKNVEFL EVLFQGPGSG SWSHPQFEKG SGSWSHPQFE K

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Macromolecule #2: Anti-RON nanobody

MacromoleculeName: Anti-RON nanobody / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 15.207868 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVQSGGG LVQAGGSLRL SCAASVRFFS INTMGWYRQA PGKQRELVAD ITSSGSTNYA DSGKGRFTIS RDNAKNTVYL QMNRLKPED TAVYYCHADY KYTTHNTAWG QGTQVTVSSG RPLEVLFQGP HHHHHHHH

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Macromolecule #3: (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid

MacromoleculeName: (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
type: ligand / ID: 3 / Number of copies: 2 / Formula: 40F
Molecular weightTheoretical: 185.177 Da
Chemical component information

ChemComp-40F:
(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid / Eglumetad

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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 K2 QUANTUM (4k x 4k) / Average electron dose: 1.75 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 365101

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