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- EMDB-31536: Thermostabilised full length human mGluR5-5M bound with L-quisqua... -

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Basic information

Entry
Database: EMDB / ID: EMD-31536
TitleThermostabilised full length human mGluR5-5M bound with L-quisqualic acid
Map dataThe primary map is the map from Relion after post processing with a shape mask and sharpened with a B-factor of -61 A2
Sample
  • Complex: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agonist bound state
    • Protein or peptide: Metabotropic glutamate receptor 5
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
  • Ligand: CHOLESTEROL HEMISUCCINATE
Function / homology
Function and homology information


A2A adenosine receptor binding / regulation of translational elongation / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / positive regulation of long-term neuronal synaptic plasticity / : / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway ...A2A adenosine receptor binding / regulation of translational elongation / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / positive regulation of long-term neuronal synaptic plasticity / : / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / protein kinase C-activating G protein-coupled receptor signaling pathway / glutamate receptor activity / Neurexins and neuroligins / protein tyrosine kinase activator activity / : / positive regulation of protein tyrosine kinase activity / regulation of synaptic transmission, glutamatergic / protein tyrosine kinase binding / dendritic shaft / locomotory behavior / learning / G protein-coupled receptor activity / postsynaptic density membrane / synapse organization / regulation of protein phosphorylation / Schaffer collateral - CA1 synapse / cognition / cellular response to amyloid-beta / regulation of translation / chemical synaptic transmission / G alpha (q) signalling events / dendritic spine / positive regulation of MAPK cascade / learning or memory / glutamatergic synapse / regulation of DNA-templated transcription / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 5 / Metabotropic glutamate receptor, Homer-binding domain / Homer-binding domain of metabotropic glutamate receptor / GluR_Homer-bdg / 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 ...GPCR, family 3, metabotropic glutamate receptor 5 / Metabotropic glutamate receptor, Homer-binding domain / Homer-binding domain of metabotropic glutamate receptor / GluR_Homer-bdg / 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 / 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. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsVinothkumar KR / Cannone G / Lebon G
Funding support India, United Kingdom, France, 5 items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)DBT/PR12422/MED/31/287/2014 India
Science and Engineering Research Board (SERB)RJN-094/2017 India
Medical Research Council (MRC, United Kingdom)MC-U105184322 United Kingdom
Agence Nationale de la Recherche (ANR)ANR-17-CE18-0001 France
Agence Nationale de la Recherche (ANR)ANR-18-CE11-0001 France
CitationJournal: Cell Rep / Year: 2021
Title: Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.
Authors: Chady Nasrallah / Giuseppe Cannone / Julie Briot / Karine Rottier / Alice E Berizzi / Chia-Ying Huang / Robert B Quast / Francois Hoh / Jean-Louis Banères / Fanny Malhaire / Ludovic Berto / ...Authors: Chady Nasrallah / Giuseppe Cannone / Julie Briot / Karine Rottier / Alice E Berizzi / Chia-Ying Huang / Robert B Quast / Francois Hoh / Jean-Louis Banères / Fanny Malhaire / Ludovic Berto / Anaëlle Dumazer / Joan Font-Ingles / Xavier Gómez-Santacana / Juanlo Catena / Julie Kniazeff / Cyril Goudet / Amadeu Llebaria / Jean-Philippe Pin / Kutti R Vinothkumar / Guillaume Lebon /
Abstract: Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus ...Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus flytrap domain is regulated by positive (PAM) or negative (NAM) allosteric modulators binding to the 7-transmembrane domain (7TM). We report the cryo-electron microscopy structures of fully inactive and intermediate-active conformations of mGlu receptor bound to an antagonist and a NAM or an agonist and a PAM, respectively, as well as the crystal structure of the 7TM bound to a photoswitchable NAM. The agonist induces a large movement between the subunits, bringing the 7TMs together and stabilizing a 7TM conformation structurally similar to the inactive state. Using functional approaches, we demonstrate that the PAM stabilizes a 7TM active conformation independent of the conformational changes induced by agonists, representing an alternative mode of mGlu activation. These findings provide a structural basis for different mGluR activation modes.
History
DepositionJul 16, 2021-
Header (metadata) releaseSep 8, 2021-
Map releaseSep 8, 2021-
UpdateOct 13, 2021-
Current statusOct 13, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.013
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  • Surface view with fitted model
  • Atomic models: PDB-7fd8
  • Surface level: 0.013
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31536.png

Downloads & links

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Map

FileDownload / File: emd_31536.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThe primary map is the map from Relion after post processing with a shape mask and sharpened with a B-factor of -61 A2
Voxel sizeX=Y=Z: 0.89 Å
Density
Contour LevelBy AUTHOR: 0.013 / Movie #1: 0.013
Minimum - Maximum-0.017614935 - 0.048680775
Average (Standard dev.)0.00011462212 (±0.001491383)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 341.76 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.890.890.89
M x/y/z384384384
origin x/y/z0.0000.0000.000
length x/y/z341.760341.760341.760
α/β/γ90.00090.00090.000
start NX/NY/NZ-40-113-15
NX/NY/NZ10616274
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS384384384
D min/max/mean-0.0180.0490.000

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Supplemental data

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Additional map: Postprocessed map with a B-factor of -122A2 (estimated...

Fileemd_31536_additional_1.map
AnnotationPostprocessed map with a B-factor of -122A2 (estimated automatically in relion), used during model building
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Postprocessed map with a B-factor of -20A2, used...

Fileemd_31536_additional_2.map
AnnotationPostprocessed map with a B-factor of -20A2, used during model building
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: one of the half map from refinement

Fileemd_31536_half_map_1.map
Annotationone of the half map from refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: one of the half map from refinement

Fileemd_31536_half_map_2.map
Annotationone of the half map from refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agon...

EntireName: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agonist bound state
Components
  • Complex: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agonist bound state
    • Protein or peptide: Metabotropic glutamate receptor 5
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agon...

SupramoleculeName: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agonist bound state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293S GnTI- / Recombinant plasmid: BacMam
Molecular weightTheoretical: 194 KDa

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Macromolecule #1: Metabotropic glutamate receptor 5

MacromoleculeName: Metabotropic glutamate receptor 5 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 96.953977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKHH HHHHHHHHLE VLFQGPQSSE RRVVAHMPGD IIIGALFSVH HQPTVDKVHE RKCGAVREQY GIQRVEAMLH TLERINSDP TLLPNITLGC EIRDSCWHSA VALEQSIEFI RDSLISSEEE EGLVRCVDGS SSSFRSKKPI VGVIGPGSSS V AIQVQNLL ...String:
DYKDDDDKHH HHHHHHHHLE VLFQGPQSSE RRVVAHMPGD IIIGALFSVH HQPTVDKVHE RKCGAVREQY GIQRVEAMLH TLERINSDP TLLPNITLGC EIRDSCWHSA VALEQSIEFI RDSLISSEEE EGLVRCVDGS SSSFRSKKPI VGVIGPGSSS V AIQVQNLL QLFNIPQIAY SATSMDLSDK TLFKYFMRVV PSDAQQARAM VDIVKRYNWT YVSAVHTEGN YGESGMEAFK DM SAKEGIC IAHSYKIYSN AGEQSFDKLL KKLTSHLPKA RVVACFCEGM TVRGLLMAMR RLGLAGEFLL LGSDGWADRY DVT DGYQRE AVGGITIKLQ SPDVKWFDDY YLKLRPETNL RNPWFQEFWQ HRFQCRLEGF PQENSKYNKT CNSSLTLKTH HVQD SKMGF VINAIYSMAY GLHNMQMSLC PGYAGLCDAM KPIDGRKLLE SLMKTAFTGV SGDTILFDEN GDSPGRYEIM NFKEM GKDY FDYINVGSWD NGELKMDDDE VWSKKSNIIR SVCSEPCEKG QIKVIRKGEV SCCWTCTPCK ENEYVFDEYT CKACQL GSW PTDDLTGCDL IPVQYLRWGD PEPIAAVVFA CLGLLATLFV TVVFIIYRDT PVVKSSSREL CYIILAGICL GYLCTFC LI AKPKQIYCYL QRIGIGLSPA MSYSALVTKT NRIARILAGS KKKICTKKPR FMSACAQLVI AFILICIQLG IIVALFIM E PPDIMHDYPS IREVYLICNT TNLGVVAPLG YNGLLILACT FYAFKTRNVP ANFNEAKYIA FAMYTTCIIW LAFVPIYFG SNYKAITMCF SVSLSATVLL GCMFVPKVYI ILAKPERNVR SAFTTSTVVR MHVGDGKSSS AA

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / 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 #3: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID

MacromoleculeName: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
type: ligand / ID: 3 / Number of copies: 2 / Formula: QUS
Molecular weightTheoretical: 189.126 Da
Chemical component information

ChemComp-QUS:
(S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID / agonist*YM / Quisqualic acid

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration2.85 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
25.0 mMHepes
150.0 mMSodium ChlorideNaClSodium chloride
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.02 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV / Details: Blot force was 10, 3.5 seconds blotting time.
DetailsmGluR5 with L-quisqualic acid and ago PAM (VU0424464) purified in DDM/CHS

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 44500 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Details: Imaging was done in EFTEM mode. Images were collected using beam shift in a series of 3x3 holes before stage shift. Active beam tilt compensation was turned on during the acquisition.
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Sampling interval: 5.0 µm / Number grids imaged: 1 / Number real images: 14604 / Average exposure time: 9.0 sec. / Average electron dose: 67.0 e/Å2
Details: Dose rate was 5.894 e/p/s. Total number of frames is 48 and each frame had a dose of 1.39 e/A2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 655344
CTF correctionSoftware - Name: CTFFIND (ver. 4)
Startup modelType of model: OTHER / Details: Using Stochastic gradient descent within Relion
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final 3D classificationNumber classes: 5 / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionNumber classes used: 3 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 118016
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

7p2l

chain_id: A, residue_range: 578-827

6n50

chain_id: A, residue_range: 25-510

6n51

chain_id: A, residue_range: 510-568
DetailsRefinement was performed with jelly body restraints
RefinementSpace: RECIPROCAL / Protocol: OTHER / Overall B value: 113.4
Output model

PDB-7fd8:
Thermostabilised full length human mGluR5-5M bound with L-quisqualic acid

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