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- EMDB-36170: Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341... -

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Entry
Database: EMDB / ID: EMD-36170
TitleCryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341495, NAM563, and LY2389575 (dimerization mode III)
Map data
Sample
  • Complex: mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575
    • Protein or peptide: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A
    • Protein or peptide: Metabotropic glutamate receptor 3,Serine/threonine-protein kinase mTOR
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
KeywordsComplex structure / mGlu2-3 heterodimer / 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
GPCR, family 3, metabotropic glutamate receptor 3 / GPCR, family 3, metabotropic glutamate receptor 2 / Domain of unknown function DUF3385, target of rapamycin protein / Domain of unknown function (DUF3385) / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / GPCR, family 3, metabotropic glutamate receptor ...GPCR, family 3, metabotropic glutamate receptor 3 / GPCR, family 3, metabotropic glutamate receptor 2 / Domain of unknown function DUF3385, target of rapamycin protein / Domain of unknown function (DUF3385) / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / GPCR, family 3, metabotropic glutamate receptor / Rapamycin binding domain / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein coupled receptors family 3 profile. / PIK-related kinase, FAT / FAT domain / FATC domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase mTOR / Peptidyl-prolyl cis-trans isomerase FKBP1A / Metabotropic glutamate receptor 2 / Metabotropic glutamate receptor 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang X / Wang M / Xu T / Feng Y / Han S / Lin S / Zhao Q / Wu B
Funding support China, 2 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)82121005 China
CitationJournal: 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
DepositionMay 12, 2023-
Header (metadata) releaseJun 21, 2023-
Map releaseJun 21, 2023-
UpdateOct 18, 2023-
Current statusOct 18, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36170.png

Downloads & links

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Map

FileDownload / File: emd_36170.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.071 Å
Density
Contour LevelBy AUTHOR: 0.225
Minimum - Maximum-2.6657858 - 4.2626867
Average (Standard dev.)0.000094553514 (±0.04201306)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 385.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36170_half_map_1.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: #1

Fileemd_36170_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575

EntireName: mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575
Components
  • Complex: mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575
    • Protein or peptide: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A
    • Protein or peptide: Metabotropic glutamate receptor 3,Serine/threonine-protein kinase mTOR
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

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Supramolecule #1: mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575

SupramoleculeName: mGlu2-3 heterodimer in presence of LY341495, NAM563, and LY2389575
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isome...

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.398914 KDa
Recombinant expressionOrganism: mammal environmental sample (environmental samples)
SequenceString: 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

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Macromolecule #2: Metabotropic glutamate receptor 3,Serine/threonine-protein kinase mTOR

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 112.712961 KDa
Recombinant expressionOrganism: mammal environmental sample (environmental samples)
SequenceString: 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

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #4: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

MacromoleculeName: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
type: ligand / ID: 4 / Number of copies: 2 / Formula: Z99
Molecular weightTheoretical: 353.369 Da
Chemical component information

ChemComp-Z99:
2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine / antidepressant, antagonist*YM / LY-341495

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm 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

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 749008

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