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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


positive regulation of biosynthetic process / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / positive regulation of multicellular organismal process / regulation of response to drug / regulation of glutamate secretion / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / macrolide binding / activin receptor binding ...positive regulation of biosynthetic process / adenylate cyclase-inhibiting G protein-coupled glutamate receptor signaling pathway / positive regulation of multicellular organismal process / regulation of response to drug / regulation of glutamate secretion / group II metabotropic glutamate receptor activity / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / TGFBR1 LBD Mutants in Cancer / behavioral response to nicotine / heart trabecula formation / regulation of cellular response to stress / negative regulation of adenylate cyclase activity / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / signaling receptor inhibitor activity / G protein-coupled glutamate receptor signaling pathway / glutamate secretion / neurotransmitter secretion / I-SMAD binding / Class C/3 (Metabotropic glutamate/pheromone receptors) / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / glutamate receptor activity / regulation of cell size / astrocyte projection / 'de novo' protein folding / FK506 binding / ventricular cardiac muscle tissue morphogenesis / TGF-beta receptor signaling activates SMADs / regulation of dopamine secretion / regulation of lipid metabolic process / heart morphogenesis / mTORC1-mediated signalling / Calcineurin activates NFAT / regulation of immune response / regulation of synaptic transmission, glutamatergic / phagocytic vesicle / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / supramolecular fiber organization / presynaptic modulation of chemical synaptic transmission / sarcoplasmic reticulum membrane / regulation of neuron apoptotic process / negative regulation of autophagy / T cell activation / peptidylprolyl isomerase / sarcoplasmic reticulum / peptidyl-prolyl cis-trans isomerase activity / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / response to cocaine / positive regulation of cell differentiation / calcium channel regulator activity / protein maturation / negative regulation of transforming growth factor beta receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / protein refolding / PML body / Z disc / G protein-coupled receptor activity / SARS-CoV-1 activates/modulates innate immune responses / Sensory perception of sweet, bitter, and umami (glutamate) taste / regulation of protein localization / presynapse / protein folding / presynaptic membrane / scaffold protein binding / cytoplasmic vesicle / chemical synaptic transmission / Potential therapeutics for SARS / amyloid fibril formation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G alpha (i) signalling events / positive regulation of MAPK cascade / transmembrane transporter binding / positive regulation of canonical NF-kappaB signal transduction / mitochondrial outer membrane / non-specific serine/threonine protein kinase / postsynaptic membrane / Golgi membrane / axon / lysosomal membrane / protein serine/threonine kinase activity / dendrite / endoplasmic reticulum membrane / 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 / GPCR, family 3, metabotropic glutamate receptor / : / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / 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 / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / : / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / Phosphatidylinositol 3- and 4-kinases signature 1. / 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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