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- PDB-8jcx: Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341... -
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Basic information
Entry | Database: PDB / ID: 8jcx | |||||||||
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Title | Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341495 and NAM563 (dimerization mode II) | |||||||||
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![]() | MEMBRANE PROTEIN / Complex structure / mGlu2-3 heterodimer | |||||||||
Function / homology | ![]() cellular component organization / regulation of cellular component organization / positive regulation of response to stimulus / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / TORC2 complex / activin receptor binding / TORC1 complex ...cellular component organization / regulation of cellular component organization / positive regulation of response to stimulus / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / TORC2 complex / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / behavioral response to nicotine / intracellular glutamate homeostasis / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / type I transforming growth factor beta receptor binding / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / negative regulation of activin receptor signaling pathway / heart trabecula formation / glutamate secretion / terminal cisterna / ryanodine receptor complex / I-SMAD binding / glutamate receptor activity / regulation of glutamate secretion / regulation of amyloid precursor protein catabolic process / long-term synaptic depression / protein maturation by protein folding / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / negative regulation of phosphoprotein phosphatase activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of macroautophagy / FK506 binding / regulation of dopamine secretion / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / Calcineurin activates NFAT / calcium channel regulator activity / regulation of immune response / TOR signaling / protein peptidyl-prolyl isomerization / supramolecular fiber organization / heart morphogenesis / regulation of ryanodine-sensitive calcium-release channel activity / regulation of synaptic transmission, glutamatergic / sarcoplasmic reticulum membrane / positive regulation of protein metabolic process / T cell activation / presynaptic modulation of chemical synaptic transmission / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / response to cocaine / peptidylprolyl isomerase / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / G protein-coupled receptor activity / calcium ion transmembrane transport / negative regulation of transforming growth factor beta receptor signaling pathway / Z disc / SARS-CoV-1 activates/modulates innate immune responses / regulation of protein localization / protein folding / positive regulation of protein binding / presynaptic membrane / gene expression / G alpha (i) signalling events / protein refolding / scaffold protein binding / chemical synaptic transmission / postsynaptic membrane / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / dendritic spine / postsynaptic density / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / phosphorylation / axon / protein serine/threonine kinase activity / glutamatergic synapse / dendrite / protein-containing complex binding / ATP binding / membrane / nucleus / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | |||||||||
![]() | Wang, X. / Wang, M. / Xu, T. / Feng, Y. / Han, S. / Lin, S. / Zhao, Q. / Wu, B. | |||||||||
Funding support | ![]()
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![]() | ![]() 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
Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 276.5 KB | Display | ![]() |
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-Validation report
Summary document | ![]() | 541.3 KB | Display | ![]() |
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Full document | ![]() | 552.6 KB | Display | |
Data in XML | ![]() | 29.1 KB | Display | |
Data in CIF | ![]() | 43.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 36168MC ![]() 8jcuC ![]() 8jcvC ![]() 8jcwC ![]() 8jcyC ![]() 8jczC ![]() 8jd0C ![]() 8jd1C ![]() 8jd2C ![]() 8jd3C ![]() 8jd4C ![]() 8jd5C ![]() 8jd6C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
#1: Protein | Mass: 109398.914 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: ![]() ![]() References: UniProt: Q14416, UniProt: P62942, peptidylprolyl isomerase | ||||
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#2: Protein | Mass: 112712.961 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() Production host: ![]() ![]() References: UniProt: Q14832, UniProt: A0A8V8TRG9, non-specific serine/threonine protein kinase | ||||
#3: Sugar | #4: Chemical | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: mGlu2-3 heterodimer in presence of LY341495 and NAM563 Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
CTF correction | Type: NONE | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 590649 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 78.04 Å2 | ||||||||||||||||||||||||
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