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- PDB-7fd8: Thermostabilised full length human mGluR5-5M bound with L-quisqua... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7fd8 | ||||||||||||||||||
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Title | Thermostabilised full length human mGluR5-5M bound with L-quisqualic acid | ||||||||||||||||||
![]() | Metabotropic glutamate receptor 5 | ||||||||||||||||||
![]() | MEMBRANE PROTEIN / G protein coupled receptors / Signal transduction / Metabotropic glutamate receptor 5 (GRM5) | ||||||||||||||||||
Function / homology | ![]() A2A adenosine receptor binding / 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 / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled glutamate receptor signaling pathway / astrocyte projection ...A2A adenosine receptor binding / 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 / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled glutamate receptor signaling pathway / 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 / : / regulation of synaptic transmission, glutamatergic / 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 / positive regulation of MAPK cascade / dendritic spine / learning or memory / glutamatergic synapse / dendrite / regulation of DNA-templated transcription / identical protein binding / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||||||||
Biological species | ![]() | ||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||||||||||||||
![]() | Vinothkumar, K.R. / Cannone, G. / Lebon, G. | ||||||||||||||||||
Funding support | ![]() ![]() ![]()
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![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 305.2 KB | Display | ![]() |
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PDB format | ![]() | 250.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.4 MB | Display | ![]() |
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Full document | ![]() | 1.4 MB | Display | |
Data in XML | ![]() | 60.9 KB | Display | |
Data in CIF | ![]() | 88.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 31536MC ![]() 7fd9C ![]() 7p2lC C: citing same article ( M: map data used to model this data |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 96953.977 Da / Num. of mol.: 2 / Mutation: H350L, N445A, T742A, S753A, T777A, I799A, A813L Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #2: Sugar | #3: Chemical | #4: Chemical | Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Human FL mGluR5-5M with L-quisqualic acid and PAM VU0424465, agonist bound state Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | |||||||||||||||
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Molecular weight | Value: 0.194 MDa / Experimental value: NO | |||||||||||||||
Source (natural) | Organism: ![]() | |||||||||||||||
Source (recombinant) | Organism: ![]() | |||||||||||||||
Buffer solution | pH: 7.4 | |||||||||||||||
Buffer component |
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Specimen | Conc.: 2.85 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: mGluR5 with L-quisqualic acid and ago PAM (VU0424464) purified in DDM/CHS | |||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1 | |||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K / Details: Blot force was 10, 3.5 seconds blotting time |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 130000 X / Calibrated magnification: 44500 X / Nominal defocus max: 2800 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 9 sec. / Electron dose: 67 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 14604 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 |
EM imaging optics | Energyfilter name: GIF Bioquantum 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. Energyfilter slit width: 20 eV |
Image scans | Sampling size: 5 µm / Width: 3838 / Height: 3710 / Movie frames/image: 48 |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 655344 | ||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118016 / Algorithm: FOURIER SPACE / Num. of class averages: 3 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | B value: 113.4 / Protocol: OTHER / Space: RECIPROCAL Details: Refinement was performed with jelly body restraints | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building |
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