+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36176 | |||||||||
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Title | Cryo-EM structure of Gi1-bound mGlu2-mGlu4 heterodimer | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex structure / Gi1-bound mGlu2-mGlu4 heterodimer / 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 / behavioral response to nicotine / intracellular glutamate homeostasis / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / neurotransmitter secretion ...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 / behavioral response to nicotine / intracellular glutamate homeostasis / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / neurotransmitter secretion / 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 / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of neuron apoptotic process / regulation of mitotic spindle organization / cellular response to forskolin / regulation of synaptic transmission, glutamatergic / presynaptic modulation of chemical synaptic transmission / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cocaine / Regulation of insulin secretion / 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 / response to peptide hormone / 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 / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / gene expression / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / cytoplasmic vesicle / scaffold protein binding / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / axon Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Escherichia coli (E. coli) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.6 Å | |||||||||
Authors | Wang X / Wang M / Xu T / Feng Y / Han S / Zhao Q / Wu B | |||||||||
Funding support | China, 2 items
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Citation | Journal: Cell Res / Year: 2023 Title: Structural insights into dimerization and activation of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers. Authors: Xinwei Wang / Mu Wang / Tuo Xu / Ye Feng / Qiang Shao / Shuo Han / Xiaojing Chu / Yechun Xu / Shuling Lin / Qiang Zhao / Beili Wu / Abstract: Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous ...Heterodimerization of the metabotropic glutamate receptors (mGlus) has shown importance in the functional modulation of the receptors and offers potential drug targets for treating central nervous system diseases. However, due to a lack of molecular details of the mGlu heterodimers, understanding of the mechanisms underlying mGlu heterodimerization and activation is limited. Here we report twelve cryo-electron microscopy (cryo-EM) structures of the mGlu2-mGlu3 and mGlu2-mGlu4 heterodimers in different conformational states, including inactive, intermediate inactive, intermediate active and fully active conformations. These structures provide a full picture of conformational rearrangement of mGlu2-mGlu3 upon activation. The Venus flytrap domains undergo a sequential conformational change, while the transmembrane domains exhibit a substantial rearrangement from an inactive, symmetric dimer with diverse dimerization patterns to an active, asymmetric dimer in a conserved dimerization mode. Combined with functional data, these structures reveal that stability of the inactive conformations of the subunits and the subunit-G protein interaction pattern are determinants of asymmetric signal transduction of the heterodimers. Furthermore, a novel binding site for two mGlu4 positive allosteric modulators was observed in the asymmetric dimer interfaces of the mGlu2-mGlu4 heterodimer and mGlu4 homodimer, and may serve as a drug recognition site. These findings greatly extend our knowledge about signal transduction of the mGlus. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36176.map.gz | 164.2 MB | EMDB map data format | |
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Header (meta data) | emd-36176-v30.xml emd-36176.xml | 20.5 KB 20.5 KB | Display Display | EMDB header |
Images | emd_36176.png | 42.8 KB | ||
Filedesc metadata | emd-36176.cif.gz | 7.8 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36176 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36176 | HTTPS FTP |
-Validation report
Summary document | emd_36176_validation.pdf.gz | 465.1 KB | Display | EMDB validaton report |
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Full document | emd_36176_full_validation.pdf.gz | 464.6 KB | Display | |
Data in XML | emd_36176_validation.xml.gz | 7.2 KB | Display | |
Data in CIF | emd_36176_validation.cif.gz | 8.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36176 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36176 | HTTPS FTP |
-Related structure data
Related structure data | 8jd5MC 8jcuC 8jcvC 8jcwC 8jcxC 8jcyC 8jczC 8jd0C 8jd1C 8jd2C 8jd3C 8jd4C 8jd6C C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_36176.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.071 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
+Entire : Gi1-bound mGlu2-mGlu4 heterodimer
+Supramolecule #1: Gi1-bound mGlu2-mGlu4 heterodimer
+Macromolecule #1: Metabotropic glutamate receptor 2
+Macromolecule #2: Metabotropic glutamate receptor 4
+Macromolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #6: scFv
+Macromolecule #7: 1-butyl-3-chloranyl-4-(4-phenylpiperidin-1-yl)pyridin-2-one
+Macromolecule #8: GLUTAMIC ACID
+Macromolecule #9: CHOLESTEROL
+Macromolecule #10: DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE
+Macromolecule #11: 2-acetamido-2-deoxy-beta-D-glucopyranose
+Macromolecule #12: 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiaz...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: INSILICO MODEL |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 939819 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |