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- PDB-8ss6: Structure of AMPA receptor GluA2 complex with auxiliary subunits ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8ss6 | |||||||||||||||
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Title | Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK, channel blocker spermidine and antiepileptic drug perampanel (closed state) | |||||||||||||||
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![]() | SIGNALING PROTEIN / AMPA receptor / spermidine / perampanel / cornichon-2 | |||||||||||||||
Function / homology | ![]() neurotransmitter receptor transport, postsynaptic endosome to lysosome / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / Cargo concentration in the ER / postsynaptic neurotransmitter receptor diffusion trapping / COPII-mediated vesicle transport / spine synapse / dendritic spine neck / dendritic spine head ...neurotransmitter receptor transport, postsynaptic endosome to lysosome / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / Cargo concentration in the ER / postsynaptic neurotransmitter receptor diffusion trapping / COPII-mediated vesicle transport / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / transmission of nerve impulse / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / cellular response to glycine / asymmetric synapse / regulation of receptor recycling / voltage-gated calcium channel activity / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / positive regulation of synaptic transmission / endoplasmic reticulum to Golgi vesicle-mediated transport / glutamate-gated receptor activity / presynaptic active zone membrane / response to fungicide / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cytoskeletal protein binding / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of synaptic transmission, glutamatergic / SNARE binding / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / PDZ domain binding / protein tetramerization / postsynaptic density membrane / ionotropic glutamate receptor binding / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / establishment of protein localization / ER to Golgi transport vesicle membrane / terminal bouton / receptor internalization / cerebral cortex development / synaptic vesicle membrane / synaptic vesicle / presynapse / presynaptic membrane / signaling receptor activity / amyloid-beta binding / growth cone / scaffold protein binding / chemical synaptic transmission / postsynaptic membrane / perikaryon / dendritic spine / postsynaptic density / neuron projection / axon / neuronal cell body / glutamatergic synapse / synapse / dendrite / protein-containing complex binding / endoplasmic reticulum membrane / protein kinase binding / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 Å | |||||||||||||||
![]() | Gangwar, S.P. / Yen, L.Y. / Yelshanskaya, M.V. / Sobolevsky, A.I. | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Modulation of GluA2-γ5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2. Authors: Shanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Aryeh Korman / Drew R Jones / Alexander I Sobolevsky / ![]() Abstract: Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat ...Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment. | |||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 711.4 KB | Display | ![]() |
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PDB format | ![]() | 578.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 3.2 MB | Display | ![]() |
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Full document | ![]() | 3.3 MB | Display | |
Data in XML | ![]() | 140 KB | Display | |
Data in CIF | ![]() | 191.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 40745MC ![]() 8bhfC ![]() 8ss2C ![]() 8ss3C ![]() 8ss4C ![]() 8ss5C ![]() 8ss7C ![]() 8ss8C ![]() 8ss9C ![]() 8ssaC ![]() 8ssbC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 2 types, 6 molecules ABCDEF
#1: Protein | Mass: 114978.859 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #2: Protein | Mass: 18948.420 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Non-polymers , 6 types, 46 molecules ![](data/chem/img/6ZP.gif)
![](data/chem/img/ZK1.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/SPD.gif)
![](data/chem/img/ZK1.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/SPD.gif)
#3: Chemical | ChemComp-6ZP / #4: Chemical | ChemComp-ZK1 / {[ #5: Chemical | ChemComp-PCW / #6: Chemical | ChemComp-CLR / #7: Chemical | ChemComp-NA / | #8: Chemical | ChemComp-SPD / | |
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-Details
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: GluA2-TARP gamma5-cornichon-2 / Type: COMPLEX Details: Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK, channel blocker spermidine and antiepileptic drug perampanel (closed state) Entity ID: #1-#2 / Source: MULTIPLE SOURCES | |||||||||||||||||||||||||
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Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 8 | |||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES Details: Protein extracted and purified in detergent micelle | |||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil | |||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: vitrification carried out in nitrogen atmosphere |
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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 defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106582 / Symmetry type: POINT | ||||||||||||||||||||||||
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