+Open data
-Basic information
Entry | Database: PDB / ID: 8trd | ||||||||||||
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Title | mGluR3 class 1 in the presence of the antagonist LY 341495 | ||||||||||||
Components | Metabotropic glutamate receptor 3 | ||||||||||||
Keywords | MEMBRANE PROTEIN / GPCR / synaptic protein | ||||||||||||
Function / homology | Function and homology information Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / astrocyte projection / G protein-coupled glutamate receptor signaling pathway / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission ...Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / astrocyte projection / G protein-coupled glutamate receptor signaling pathway / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission / presynaptic membrane / gene expression / scaffold protein binding / postsynaptic membrane / postsynapse / dendritic spine / postsynaptic density / neuron projection / axon / glutamatergic synapse / plasma membrane Similarity search - Function | ||||||||||||
Biological species | Rattus norvegicus (Norway rat) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||
Authors | Strauss, A. / Levitz, J. | ||||||||||||
Funding support | United States, 3items
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Citation | Journal: Nat Commun / Year: 2024 Title: Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization. Authors: Alexa Strauss / Alberto J Gonzalez-Hernandez / Joon Lee / Nohely Abreu / Purushotham Selvakumar / Leslie Salas-Estrada / Melanie Kristt / Anisul Arefin / Kevin Huynh / Dagan C Marx / Kristen ...Authors: Alexa Strauss / Alberto J Gonzalez-Hernandez / Joon Lee / Nohely Abreu / Purushotham Selvakumar / Leslie Salas-Estrada / Melanie Kristt / Anisul Arefin / Kevin Huynh / Dagan C Marx / Kristen Gilliland / Bruce J Melancon / Marta Filizola / Joel Meyerson / Joshua Levitz / Abstract: The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) ...The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited. Here we use multiple approaches to dissect the functional and structural effects of orthosteric versus allosteric ligands. We find, using electrophysiological and live cell imaging assays, that both agonists and positive allosteric modulators (PAMs) can drive activation and internalization of group II and III mGluRs. The effects of PAMs are pleiotropic, boosting the maximal response to orthosteric agonists and serving independently as internalization-biased agonists across mGluR subtypes. Motivated by this and intersubunit FRET analyses, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling. | ||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8trd.cif.gz | 290 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8trd.ent.gz | 184 KB | Display | PDB format |
PDBx/mmJSON format | 8trd.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8trd_validation.pdf.gz | 1.4 MB | Display | wwPDB validaton report |
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Full document | 8trd_full_validation.pdf.gz | 1.4 MB | Display | |
Data in XML | 8trd_validation.xml.gz | 58.7 KB | Display | |
Data in CIF | 8trd_validation.cif.gz | 87.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tr/8trd ftp://data.pdbj.org/pub/pdb/validation_reports/tr/8trd | HTTPS FTP |
-Related structure data
Related structure data | 41578MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 103161.555 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Grm3 / Production host: Homo sapiens (human) / References: UniProt: P31422 #2: 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 |
-Sample preparation
Component | Name: Metabotropic Glutamate Receptor 3 dimer / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.26 MDa / Experimental value: NO |
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 700 nm / Alignment procedure: BASIC |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 58 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
EM software | Name: PHENIX / Version: 1.21_5207 / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 84964 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL / Space: REAL | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 93.26 Å2 | ||||||||||||||||||||||||
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