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- EMDB-37975: Human FL Metabotropic glutamate receptor 5, mGlu5-5M with quisqua... -

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Basic information

Entry
Database: EMDB / ID: EMD-37975
TitleHuman FL Metabotropic glutamate receptor 5, mGlu5-5M with quisqualate and VU0424465, conformer 2
Map datacombined sharpened map
Sample
  • Complex: Human FL Metabotropic glutamate receptor 5, mGlu5-5M
    • 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: VU0424465
KeywordsG-PROTEIN COUPLED RECEPTORS / SIGNAL TRANSDUCTION / METABOTROPIC GLUTAMATE RECEPTOR / Agonist / active state / MEMBRANE PROTEIN
Function / homology
Function and homology information


A2A adenosine receptor binding / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of long-term neuronal synaptic plasticity / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity ...A2A adenosine receptor binding / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of long-term neuronal synaptic plasticity / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / Neurexins and neuroligins / astrocyte projection / protein tyrosine kinase activator activity / regulation of synaptic transmission, glutamatergic / positive regulation of calcium-mediated signaling / protein tyrosine kinase binding / dendritic shaft / learning / locomotory behavior / G protein-coupled receptor activity / postsynaptic density membrane / synapse organization / Schaffer collateral - CA1 synapse / cognition / cellular response to amyloid-beta / G alpha (q) signalling events / chemical synaptic transmission / dendritic spine / learning or memory / positive regulation of MAPK cascade / neuronal cell body / dendrite / regulation of DNA-templated transcription / glutamatergic synapse / 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 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain ...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 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 / 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: 3.5 Å
AuthorsLebon G / Cannone G / Vinothkumar KR
Funding support India, France, 3 items
OrganizationGrant numberCountry
Department of Biotechnology (DBT, India)DBT/PR12422/MED/31/287/204 India
Other governmentRTI4006
Agence Nationale de la Recherche (ANR)ANR-20-CE11-0019 France
CitationJournal: Nat Commun / Year: 2025
Title: Conformational diversity in class C GPCR positive allosteric modulation.
Authors: Giuseppe Cannone / Ludovic Berto / Fanny Malhaire / Gavin Ferguson / Aurelien Fouillen / Stéphanie Balor / Joan Font-Ingles / Amadeu Llebaria / Cyril Goudet / Abhay Kotecha / Vinothkumar K ...Authors: Giuseppe Cannone / Ludovic Berto / Fanny Malhaire / Gavin Ferguson / Aurelien Fouillen / Stéphanie Balor / Joan Font-Ingles / Amadeu Llebaria / Cyril Goudet / Abhay Kotecha / Vinothkumar K R / Guillaume Lebon /
Abstract: The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture ...The metabotropic glutamate receptors (mGlus) are class C G protein-coupled receptors (GPCR) that form obligate dimers activated by the major excitatory neurotransmitter L-glutamate. The architecture of mGlu receptor comprises an extracellular Venus-Fly Trap domain (VFT) connected to the transmembrane domain (7TM) through a Cysteine-Rich Domain (CRD). The binding of L-glutamate in the VFTs and subsequent conformational change results in the signal being transmitted to the 7TM inducing G protein binding and activation. The mGlu receptors signal transduction can be allosterically potentiated by positive allosteric modulators (PAMs) binding to the 7TMs, which are of therapeutic interest in various neurological disorders. Here, we report the cryoEM structures of metabotropic glutamate receptor 5 (mGlu) purified with three chemically and pharmacologically distinct PAMs. We find that the PAMs modulate the receptor equilibrium through their different binding modes, revealing how their interactions in the 7TMs impact the mGlu receptor conformational landscape and function. In addition, we identified a PAM-free but agonist-bound intermediate state that also reveals interactions mediated by intracellular loop 2. The activation of mGlu receptor is a multi-step process in which the binding of the PAMs in the 7TM modulates the equilibrium towards the active state.
History
DepositionNov 4, 2023-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37975.png

Downloads & links

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Map

FileDownload / File: emd_37975.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcombined sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.02 Å/pix.
x 256 pix.
= 261.783 Å		1.02 Å/pix.
x 256 pix.
= 261.783 Å		1.02 Å/pix.
x 256 pix.
= 261.783 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.02259 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-0.9471299 - 1.6489488
Average (Standard dev.)0.0012505722 (±0.07512293)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 261.78305 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: DeepEMhancer map used during model building

Fileemd_37975_additional_1.map
AnnotationDeepEMhancer map used during model building
Projections & Slices
AxesZYX

Projections

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Density Histograms

Histogram

Histogram (log scale)

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Half map: One of the half maps

Fileemd_37975_half_map_1.map
AnnotationOne of the half maps
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: One of the half maps

Fileemd_37975_half_map_2.map
AnnotationOne of the half maps
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human FL Metabotropic glutamate receptor 5, mGlu5-5M

EntireName: Human FL Metabotropic glutamate receptor 5, mGlu5-5M
Components
  • Complex: Human FL Metabotropic glutamate receptor 5, mGlu5-5M
    • 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: VU0424465

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Supramolecule #1: Human FL Metabotropic glutamate receptor 5, mGlu5-5M

SupramoleculeName: Human FL Metabotropic glutamate receptor 5, mGlu5-5M / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Receptor purified in detergent micelles with agonist quisqualate and PAM
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Metabotropic glutamate receptor 5

MacromoleculeName: Metabotropic glutamate receptor 5 / type: protein_or_peptide / ID: 1
Details: The construct has tags and protease cleavage site at its N-term (DYKDDDDKHHHHHHHHHHLEVLFQGP) and when compared to uniprot it starts at 21 and ends at 856. For CryoEM, the tag is cleaved and ...Details: The construct has tags and protease cleavage site at its N-term (DYKDDDDKHHHHHHHHHHLEVLFQGP) and when compared to uniprot it starts at 21 and ends at 856. For CryoEM, the tag is cleaved and the protein used for experiment starts at QSSE but residues starting RR have been modeled. There are 5 thermostabilising mutations (T742A, S753A, T777A, I799A, A813L). Residue N445 is mutated to remove glycosylation. An additional mutation H350L is engineered for a nanobody to bind. Each monomer has one sugar modeled and 10 disulfide bonds.
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.691492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSSERRVVAH MPGDIIIGAL FSVHHQPTVD KVHERKCGAV REQYGIQRVE AMLHTLERIN SDPTLLPNIT LGCEIRDSCW HSAVALEQS IEFIRDSLIS SEEEEGLVRC VDGSSSSFRS KKPIVGVIGP GSSSVAIQVQ NLLQLFNIPQ IAYSATSMDL S DKTLFKYF ...String:
QSSERRVVAH MPGDIIIGAL FSVHHQPTVD KVHERKCGAV REQYGIQRVE AMLHTLERIN SDPTLLPNIT LGCEIRDSCW HSAVALEQS IEFIRDSLIS SEEEEGLVRC VDGSSSSFRS KKPIVGVIGP GSSSVAIQVQ NLLQLFNIPQ IAYSATSMDL S DKTLFKYF MRVVPSDAQQ ARAMVDIVKR YNWTYVSAVH TEGNYGESGM EAFKDMSAKE GICIAHSYKI YSNAGEQSFD KL LKKLTSH LPKARVVACF CEGMTVRGLL MAMRRLGLAG EFLLLGSDGW ADRYDVTDGY QREAVGGITI KLQSPDVKWF DDY YLKLRP ETNLRNPWFQ EFWQHRFQCR LEGFPQENSK YNKTCNSSLT LKTHHVQDSK MGFVINAIYS MAYGLHNMQM SLCP GYAGL CDAMKPIDGR KLLESLMKTA FTGVSGDTIL FDENGDSPGR YEIMNFKEMG KDYFDYINVG SWDNGELKMD DDEVW SKKS NIIRSVCSEP CEKGQIKVIR KGEVSCCWTC TPCKENEYVF DEYTCKACQL GSWPTDDLTG CDLIPVQYLR WGDPEP IAA VVFACLGLLA TLFVTVVFII YRDTPVVKSS SRELCYIILA GICLGYLCTF CLIAKPKQIY CYLQRIGIGL SPAMSYS AL VTKTNRIARI LAGSKKKICT KKPRFMSACA QLVIAFILIC IQLGIIVALF IMEPPDIMHD YPSIREVYLI CNTTNLGV V APLGYNGLLI LACTFYAFKT RNVPANFNEA KYIAFAMYTT CIIWLAFVPI YFGSNYKAIT MCFSVSLSAT VLLGCMFVP KVYIILAKPE RNVRSAFTTS TVVRMHVGDG KSSSAA

UniProtKB: Metabotropic glutamate receptor 5

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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

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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

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Macromolecule #4: VU0424465

MacromoleculeName: VU0424465 / type: ligand / ID: 4 / Number of copies: 2 / Formula: XQT
Molecular weightTheoretical: 326.365 Da

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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

Concentration6 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
25.0 mMHEPES
150.0 mMsodium chloride
0.03 %dodecyl maltpside
0.006 %cholesterol hemisuccinate
GridModel: Quantifoil R0.6/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV / Details: Blotting time of 5 seconds and blot force of 10.
DetailsReceptor is purified in detergent micelles and monodisperse. The receptor is purified with 10 uM Quisqualate and 10 uM PAM VU0424465

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Electron microscopy

MicroscopeFEI TITAN KRIOS
DetailsImages were collected with Aberration-free image shift and Fringe-free imaging with a Selectris energy filter in EFTEM mode
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Number real images: 19115 / Average exposure time: 4.9 sec. / Average electron dose: 50.0 e/Å2 / Details: Electron flux was 5.4 /e/A2/s. No. of frames 1566
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 192572 / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4481289
Startup modelType of model: OTHER
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 41886
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

2377


Chain - Chain ID: A / Chain - Source name: Other / Chain - Initial model type: other
Details: The model which is being curated was used as initial template
RefinementSpace: RECIPROCAL / Protocol: OTHER / Overall B value: 95.3
Output model

PDB-8x0d:
Human FL Metabotropic glutamate receptor 5, mGlu5-5M with quisqualate and VU0424465, conformer 2

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