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- PDB-8jcw: Cryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341... -

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Entry
Database: PDB / ID: 8jcw
TitleCryo-EM structure of mGlu2-mGlu3 heterodimer in presence of LY341495 and NAM563 (dimerization mode I)
Components
  • Metabotropic glutamate receptor 2,Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Metabotropic glutamate receptor 3,Serine/threonine-protein kinase mTOR
KeywordsMEMBRANE PROTEIN / Complex structure / mGlu2-3 heterodimer
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
CHOLESTEROL / Chem-Z99 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 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

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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
3: Metabotropic glutamate receptor 3,Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)224,0348
Polymers222,1122
Non-polymers1,9226
Water0
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 3,Serine/threonine-protein kinase mTOR / mGluR3


Mass: 112712.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM3, GPRC1C, MGLUR3, MTOR
Production host: mammal environmental sample (environmental samples)
References: UniProt: Q14832, 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / 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-Z99 / 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine / (1S,2S)-2-[(2S)-2-amino-1-hydroxy-1-oxo-3-(9H-xanthen-9-yl)propan-2-yl]cyclopropane-1-carboxylic acid / LY-341495


Mass: 353.369 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H19NO5 / Feature type: SUBJECT OF INVESTIGATION / Comment: antidepressant, antagonist*YM
#5: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
Has ligand of interestY

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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: mGlu2-3 heterodimer in presence of LY341495 and NAM563
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 FIELDBright-field microscopy / 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: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 516615 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 65.76 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002510992
ELECTRON MICROSCOPYf_angle_d0.573415054
ELECTRON MICROSCOPYf_chiral_restr0.04521756
ELECTRON MICROSCOPYf_plane_restr0.00411974
ELECTRON MICROSCOPYf_dihedral_angle_d12.42953623

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