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Yorodumi- EMDB-36171: Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of NAM563 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36171 | |||||||||
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Title | Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of NAM563 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Complex structure / mGlu2-3 heterodimer in presence of NAM563 / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information positive regulation of response to stimulus / regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / response to chemical / regulation of cellular response to stress / macrolide binding / TORC1 complex / activin receptor binding / cytoplasmic side of membrane ...positive regulation of response to stimulus / regulation of cellular component organization / regulation of response to drug / group II metabotropic glutamate receptor activity / response to chemical / regulation of cellular response to stress / macrolide binding / TORC1 complex / activin receptor binding / cytoplasmic side of membrane / behavioral response to nicotine / G protein-coupled glutamate receptor signaling pathway / intracellular glutamate homeostasis / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / signaling receptor inhibitor activity / astrocyte projection / type I transforming growth factor beta receptor binding / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / negative regulation of activin receptor signaling pathway / heart trabecula formation / glutamate secretion / terminal cisterna / ryanodine receptor complex / glutamate receptor activity / regulation of glutamate secretion / I-SMAD binding / regulation of amyloid precursor protein catabolic process / long-term synaptic depression / protein maturation by protein folding / 'de novo' protein folding / ventricular cardiac muscle tissue morphogenesis / negative regulation of phosphoprotein phosphatase activity / FK506 binding / postsynaptic modulation of chemical synaptic transmission / regulation of dopamine secretion / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / calcium channel regulator activity / Calcineurin activates NFAT / regulation of immune response / 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 / presynaptic modulation of chemical synaptic transmission / positive regulation of protein metabolic process / T cell activation / negative regulation of autophagy / response to cocaine / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum / peptidylprolyl isomerase / 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 / presynaptic membrane / gene expression / positive regulation of protein binding / G alpha (i) signalling events / protein refolding / chemical synaptic transmission / scaffold protein binding / postsynaptic membrane / positive regulation of canonical NF-kappaB signal transduction / Potential therapeutics for SARS / transmembrane transporter binding / amyloid fibril formation / dendritic spine / postsynaptic density / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / axon / phosphorylation / protein serine/threonine kinase activity / dendrite / glutamatergic synapse / protein-containing complex binding / ATP binding / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Wang X / Wang M / Xu T / Feng Y / Han S / Lin 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_36171.map.gz | 168.1 MB | EMDB map data format | |
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Header (meta data) | emd-36171-v30.xml emd-36171.xml | 18.1 KB 18.1 KB | Display Display | EMDB header |
Images | emd_36171.png | 47.2 KB | ||
Filedesc metadata | emd-36171.cif.gz | 6.8 KB | ||
Others | emd_36171_half_map_1.map.gz emd_36171_half_map_2.map.gz | 165.2 MB 165.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36171 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36171 | HTTPS FTP |
-Related structure data
Related structure data | 8jd0MC 8jcuC 8jcvC 8jcwC 8jcxC 8jcyC 8jczC 8jd1C 8jd2C 8jd3C 8jd4C 8jd5C 8jd6C M: atomic model generated by this map C: citing same article (ref.) |
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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_36171.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
-Half map: #2
File | emd_36171_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36171_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : mGlu2-3 heterodimer in presence of NAM563
Entire | Name: mGlu2-3 heterodimer in presence of NAM563 |
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Components |
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-Supramolecule #1: mGlu2-3 heterodimer in presence of NAM563
Supramolecule | Name: mGlu2-3 heterodimer in presence of NAM563 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: Homo sapiens (human) |
-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: Homo sapiens (human) |
Molecular weight | Theoretical: 109.398914 KDa |
Recombinant expression | Organism: mammal environmental sample (environmental samples) |
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 3,Serine/threonine-protein kinase mTOR
Macromolecule | Name: Metabotropic glutamate receptor 3,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: Homo sapiens (human) |
Molecular weight | Theoretical: 112.712961 KDa |
Recombinant expression | Organism: mammal environmental sample (environmental samples) |
Sequence | String: DYKDDDDKGA PWSHPQFEKG SGSWSHPQFE KLGDHNFLRR EIKIEGDLVL GGLFPINEKG TGTEECGRIN EDRGIQRLEA MLFAIDEIN KDDYLLPGVK LGVHILDTCS RDTYALEQSL EFVRASLTKV DEAEYMCPDG SYAIQENIPL LIAGVIGGSY S SVSIQVAN ...String: DYKDDDDKGA PWSHPQFEKG SGSWSHPQFE KLGDHNFLRR EIKIEGDLVL GGLFPINEKG TGTEECGRIN EDRGIQRLEA MLFAIDEIN KDDYLLPGVK LGVHILDTCS RDTYALEQSL EFVRASLTKV DEAEYMCPDG SYAIQENIPL LIAGVIGGSY S SVSIQVAN LLRLFQIPQI SYASTSAKLS DKSRYDYFAR TVPPDFYQAK AMAEILRFFN WTYVSTVASE GDYGETGIEA FE QEARLRN ICIATAEKVG RSNIRKSYDS VIRELLQKPN ARVVVLFMRS DDSRELIAAA SRANASFTWV ASDGWGAQES IIK GSEHVA YGAITLELAS QPVRQFDRYF QSLNPYNNHR NPWFRDFWEQ KFQCSLQNKR NHRRVCDKHL AIDSSNYEQE SKIM FVVNA VYAMAHALHK MQRTLCPNTT KLCDAMKILD GKKLYKDYLL KINFTAPFNP NKDADSIVKF DTFGDGMGRY NVFNF QNVG GKYSYLKVGH WAETLSLDVN SIHWSRNSVP TSQCSDPCAP NEMKNMQPGD VCCWICIPCE PYEYLADEFT CMDCGS GQW PTADLTGCYD LPEDYIRWED AWAIGPVTIA CLGFMCTCMV VTVFIKHNNT PLVKASGREL CYILLFGVGL SYCMTFF FI AKPSPVICAL RRLGLGSSFA ICYSALLTKT NCIARIFDGV KNGAQRPKFI SPSSQVFICL GLILVQIVMV SVWLILEA P GTRRYTLAEK RETVILKCNV KDSSMLISLT YDVILVILCT VYAFKTRKCP ENFNEAKFIG FTMYTTCIIW LAFLPIFYV TSSDYRVQTT TMCISVSLSG FVVLGCLFAP KVHIILFQPQ KNVVTHRLHL NRFSVSGTGT TYSQSSASTY VPTVCNGREV LDSTTSSLL EVLFQGPAIL WHEMWHEGLE EASRLYFGER NVKGMFEVLE PLHAMMERGP QTLKETSFNQ AYGRDLMEAQ E WCRKYMKS GNVKDLTQAW DLYYHVFRRI SKQEF UniProtKB: Metabotropic glutamate receptor 3, 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: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #4: 4-(1-methylpyrazol-4-yl)-7-[[(2~{S})-2-(trifluoromethyl)morpholin...
Macromolecule | Name: 4-(1-methylpyrazol-4-yl)-7-[[(2~{S})-2-(trifluoromethyl)morpholin-4-yl]methyl]quinoline-2-carboxamide type: ligand / ID: 4 / Number of copies: 1 / Formula: J9R |
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Molecular weight | Theoretical: 419.4 Da |
Chemical component information | ChemComp-J9R: |
-Macromolecule #5: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 9 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #6: GLUTAMIC ACID
Macromolecule | Name: GLUTAMIC ACID / type: ligand / ID: 6 / Number of copies: 1 / 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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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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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 70.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: INSILICO MODEL |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 460025 |