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- EMDB-36175: Cryo-EM structure of G protein-free mGlu2-mGlu4 heterodimer in Ac... -
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Open data
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Basic information
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Title | Cryo-EM structure of G protein-free mGlu2-mGlu4 heterodimer in Acc state | |||||||||
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![]() | Complex structure / mGlu2-mGlu4 heterodimer / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / 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 / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / regulation of cellular response to stress / macrolide binding / TORC2 complex ...adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / 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 / adenylate cyclase inhibiting G protein-coupled 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) / neurotransmitter secretion / 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 / 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 / regulation of neuron apoptotic process / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Z disc / SARS-CoV-1 activates/modulates innate immune responses / regulation of protein localization / protein folding / presynapse / positive regulation of protein binding / presynaptic membrane / gene expression / G alpha (i) signalling events / cytoplasmic vesicle / protein refolding / scaffold protein binding / chemical synaptic transmission / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / positive regulation of MAPK cascade / 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 | 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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 168 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.4 KB 17.4 KB | Display Display | ![]() |
Images | ![]() | 65.6 KB | ||
Filedesc metadata | ![]() | 6.8 KB | ||
Others | ![]() ![]() | 164.9 MB 164.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 752.1 KB | Display | ![]() |
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Full document | ![]() | 751.7 KB | Display | |
Data in XML | ![]() | 15.1 KB | Display | |
Data in CIF | ![]() | 17.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8jd4MC ![]() 8jcuC ![]() 8jcvC ![]() 8jcwC ![]() 8jcxC ![]() 8jcyC ![]() 8jczC ![]() 8jd0C ![]() 8jd1C ![]() 8jd2C ![]() 8jd3C ![]() 8jd5C ![]() 8jd6C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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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
-Half map: #2
File | emd_36175_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36175_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, a...
Entire | Name: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, and ADX88178 |
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Components |
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-Supramolecule #1: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, a...
Supramolecule | Name: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, and ADX88178 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isome...
Macromolecule | Name: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: peptidylprolyl isomerase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 109.398914 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 LTKTNRIARI FGGAREGAQR PRFISPASQV AICLALISGQ LLIVVAWLVV EAPGTGKETA PERREVVTLR CNHRDASM L GSLAYNVLLI ALCTLYAFKT RKCPENFNEA KFIGFTMYTT CIIWLAFLPI FYVTSSDYRV QTTTMCVSVS LSGSVVLGC LFAPKLHIIL FQPQKNVVSH RAPTSRFGSA AARASSSLGQ GSGSQFVPTV CNGREVVDST TSSLLEVLFQ GPGVQVETIS PGDGRTFPK RGQTCVVHYT GMLEDGKKFD SSRDRNKPFK FMLGKQEVIR GWEEGVAQMS VGQRAKLTIS PDYAYGATGH P GIIPPHAT LVFDVELLKL EFAAAHHHHH HHHHH UniProtKB: Metabotropic glutamate receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1A |
-Macromolecule #2: Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR
Macromolecule | Name: Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: non-specific serine/threonine protein kinase |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 114.187086 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DYKDDDDGAP WSHPQFEKGS GSWSHPQFEK KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINN DPDLLPNITL GARILDTCSR DTHALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV S IMVANILR ...String: DYKDDDDGAP WSHPQFEKGS GSWSHPQFEK KPKGHPHMNS IRIDGDITLG GLFPVHGRGS EGKPCGELKK EKGIHRLEAM LFALDRINN DPDLLPNITL GARILDTCSR DTHALEQSLT FVQALIEKDG TEVRCGSGGP PIITKPERVV GVIGASGSSV S IMVANILR LFKIPQISYA STAPDLSDNS RYDFFSRVVP SDTYQAQAMV DIVRALKWNY VSTVASEGSY GESGVEAFIQ KS REDGGVC IAQSVKIPRE PKAGEFDKII RRLLETSNAR AVIIFANEDD IRRVLEAARR ANQTGHFFWM GSDSWGSKIA PVL HLEEVA EGAVTILPKR MSVRGFDRYF SSRTLDNNRR NIWFAEFWED NFHCKLSRHA LKKGSHVKKC TNRERIGQDS AYEQ EGKVQ FVIDAVYAMG HALHAMHRDL CPGRVGLCPR MDPVDGTQLL KYIRNVNFSG IAGNPVTFNE NGDAPGRYDI YQYQL RNDS AEYKVIGSWT DHLHLRIERM HWPGSGQQLP RSICSLPCQP GERKKTVKGM PCCWHCEPCT GYQYQVDRYT CKTCPY DMR PTENRTGCRP IPIIKLEWGS PWAVLPLFLA VVGIAATLFV VITFVRYNDT PIVKASGREL SYVLLAGIFL CYATTFL MI AEPDLGTCSL RRIFLGLGMS ISYAALLTKT NRIYRIFEQG KRSVSAPRFI SPASQLAITF SLISLQLLGI CVWFVVDP S HSVVDFQDQR TLDPRFARGV LKCDISDLSL ICLLGYSMLL MVTCTVYAIK TRGVPETFNE AKPIGFTMYT TCIVWLAFI PIFFGTSQSA DKLYIQTTTL TVSVSLSASV SLGMLYMPKV YIILFHPEQN VPKRKRSLKA VVTAATMSNK FTQKGNFRPN GEAKSELCE NLEAPALATK QTYVTYTNHA ILEVLFQGPA ILWHEMWHEG LEEASRLYFG ERNVKGMFEV LEPLHAMMER G PQTLKETS FNQAYGRDLM EAQEWCRKYM KSGNVKDLTQ AWDLYYHVFR RISKQ UniProtKB: Metabotropic glutamate receptor 4, Serine/threonine-protein kinase mTOR |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 3 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: GLUTAMIC ACID
Macromolecule | Name: GLUTAMIC ACID / type: ligand / ID: 4 / Number of copies: 2 / Formula: GLU |
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Molecular weight | Theoretical: 147.129 Da |
Chemical component information | ![]() ChemComp-GLU: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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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: ![]() |
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 |
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Image processing
Startup model | Type of model: INSILICO MODEL |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 653804 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |