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- PDB-8jd4: Cryo-EM structure of G protein-free mGlu2-mGlu4 heterodimer in Ac... -

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Basic information

Entry
Database: PDB / ID: 8jd4
TitleCryo-EM structure of G protein-free mGlu2-mGlu4 heterodimer in Acc state
Components
  • Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR
KeywordsMEMBRANE PROTEIN / Complex structure / mGlu2-mGlu4 heterodimer
Function / homology
Function and homology information


adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / regulation of cellular component organization / 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 / activin receptor binding / TORC1 complex / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion ...adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / regulation of cellular component organization / 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 / 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 / neurotransmitter secretion / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / glutamate secretion / signaling receptor inhibitor activity / long-term synaptic depression / 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 / regulation of neuron apoptotic process / Calcineurin activates NFAT / regulation of immune response / heart morphogenesis / regulation of synaptic transmission, glutamatergic / supramolecular fiber organization / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / presynaptic modulation of chemical synaptic transmission / sarcoplasmic reticulum membrane / negative regulation of autophagy / T cell activation / protein maturation / sarcoplasmic reticulum / calcium channel regulator activity / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / response to cocaine / negative regulation of transforming growth factor beta receptor signaling pathway / G protein-coupled receptor activity / SARS-CoV-1 activates/modulates innate immune responses / Z disc / Sensory perception of sweet, bitter, and umami (glutamate) taste / protein folding / presynapse / regulation of protein localization / presynaptic membrane / protein refolding / cytoplasmic vesicle / scaffold protein binding / G alpha (i) signalling events / chemical synaptic transmission / amyloid fibril formation / Potential therapeutics for SARS / gene expression / transmembrane transporter binding / postsynaptic membrane / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / non-specific serine/threonine protein kinase / positive regulation of MAPK cascade / axon / protein serine/threonine kinase activity / dendrite / protein-containing complex binding / glutamatergic synapse / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor 2 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain ...GPCR, family 3, metabotropic glutamate receptor 4 / GPCR, family 3, metabotropic glutamate receptor 2 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / Serine/threonine-protein kinase ATR-like, HEAT repeats / GPCR, family 3, metabotropic glutamate receptor / : / 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 / G-protein coupled receptors family 3 signature 3. / GPCR, family 3, conserved site / GPCR, family 3 / G-protein coupled receptors family 3 profile. / : / FATC domain / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / : / Phosphatidylinositol 3- and 4-kinases signature 1. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / 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
GLUTAMIC ACID / Serine/threonine-protein kinase mTOR / Peptidyl-prolyl cis-trans isomerase FKBP1A / Metabotropic glutamate receptor 2 / Metabotropic glutamate receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWang, X. / Wang, M. / Xu, T. / Feng, Y. / Han, S. / Lin, S. / Zhao, Q. / Wu, B.
Funding support China, 2items
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, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 21, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
2: Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A
4: Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,5447
Polymers223,5862
Non-polymers9585
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A / mGluR2 / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506- ...mGluR2 / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 109398.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM2, GPRC1B, MGLUR2, FKBP1A, FKBP1, FKBP12
Production host: mammal environmental sample (environmental samples)
References: UniProt: Q14416, UniProt: P62942, peptidylprolyl isomerase
#2: Protein Metabotropic glutamate receptor 4,Serine/threonine-protein kinase mTOR / mGluR4


Mass: 114187.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM4, GPRC1D, MGLUR4, MTOR
Production host: mammal environmental sample (environmental samples)
References: UniProt: Q14833, UniProt: A0A8V8TRG9, non-specific serine/threonine protein kinase
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H9NO4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: mGlu2-mGlu4 heterodimer in presence of glutamate, JNJ-40411813, and ADX88178
Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: mammal environmental sample (environmental samples)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 653804 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 82.66 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002910894
ELECTRON MICROSCOPYf_angle_d0.531214874
ELECTRON MICROSCOPYf_chiral_restr0.04221737
ELECTRON MICROSCOPYf_plane_restr0.0041944
ELECTRON MICROSCOPYf_dihedral_angle_d12.18273631

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