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- PDB-8jcy: Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341... -
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Basic information
Entry | Database: PDB / ID: 8jcy | |||||||||
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Title | Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341495, NAM563, and LY2389575 (dimerization mode I) | |||||||||
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![]() | MEMBRANE PROTEIN / Complex structure / mGlu2-3 heterodimer | |||||||||
Function / homology | ![]() regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / transforming growth factor beta receptor binding ...regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / transforming growth factor beta receptor binding / intracellular glutamate homeostasis / TGFBR1 LBD Mutants in Cancer / behavioral response to nicotine / regulation of protein metabolic process / type I transforming growth factor beta receptor binding / negative regulation of adenylate cyclase activity / negative regulation of activin receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / heart trabecula formation / I-SMAD binding / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / glutamate secretion / long-term synaptic depression / signaling receptor inhibitor activity / regulation of glutamate secretion / 'de novo' protein folding / ventricular cardiac muscle tissue morphogenesis / FK506 binding / cellular response to stress / regulation of dopamine secretion / TGF-beta receptor signaling activates SMADs / mTORC1-mediated signalling / regulation of ryanodine-sensitive calcium-release channel activity / Calcineurin activates NFAT / regulation of immune response / postsynaptic modulation of chemical synaptic transmission / heart morphogenesis / regulation of synaptic transmission, glutamatergic / supramolecular fiber organization / presynaptic modulation of chemical synaptic transmission / sarcoplasmic reticulum membrane / calcium channel regulator activity / negative regulation of autophagy / T cell activation / protein maturation / sarcoplasmic reticulum / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / peptidyl-prolyl cis-trans isomerase activity / peptidylprolyl isomerase / response to cocaine / negative regulation of transforming growth factor beta receptor signaling pathway / G protein-coupled receptor activity / Z disc / SARS-CoV-1 activates/modulates innate immune responses / protein folding / regulation of protein localization / presynaptic membrane / protein refolding / scaffold protein binding / G alpha (i) signalling events / chemical synaptic transmission / dendritic spine / amyloid fibril formation / Potential therapeutics for SARS / gene expression / transmembrane transporter binding / postsynaptic membrane / positive regulation of canonical NF-kappaB signal transduction / non-specific serine/threonine protein kinase / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / postsynaptic density / axon / protein serine/threonine kinase activity / dendrite / protein-containing complex binding / glutamatergic synapse / ATP binding / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 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 | ![]() | 283.7 KB | Display | ![]() |
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PDB format | ![]() | 206.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 757.4 KB | Display | ![]() |
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Full document | ![]() | 770.1 KB | Display | |
Data in XML | ![]() | 29.9 KB | Display | |
Data in CIF | ![]() | 44.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 36169MC ![]() 8jcuC ![]() 8jcvC ![]() 8jcwC ![]() 8jcxC ![]() 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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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 | #5: Chemical | ChemComp-CLR / Has ligand of interest | Y | Has protein modification | 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, NAM563, and LY2389575 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: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1162068 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 31 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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