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- PDB-8ayl: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8ayl | ||||||||||||
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Title | Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059 | ||||||||||||
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![]() | MEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission | ||||||||||||
Function / homology | ![]() Phase 2 - plateau phase / Phase 0 - rapid depolarisation / Cargo concentration in the ER / cellular response to amine stimulus / axonal spine / COPII-mediated vesicle transport / positive regulation of membrane potential / cellular response to ammonium ion / neurotransmitter receptor transport, postsynaptic endosome to lysosome / L-type voltage-gated calcium channel complex ...Phase 2 - plateau phase / Phase 0 - rapid depolarisation / Cargo concentration in the ER / cellular response to amine stimulus / axonal spine / COPII-mediated vesicle transport / positive regulation of membrane potential / cellular response to ammonium ion / neurotransmitter receptor transport, postsynaptic endosome to lysosome / L-type voltage-gated calcium channel complex / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / LGI-ADAM interactions / myosin V binding / Trafficking of AMPA receptors / regulation of AMPA receptor activity / neuron spine / neurotransmitter receptor internalization / channel regulator activity / protein phosphatase 2B binding / response to arsenic-containing substance / cellular response to dsRNA / postsynaptic neurotransmitter receptor diffusion trapping / dendritic spine membrane / Synaptic adhesion-like molecules / glutamate-gated calcium ion channel activity / long-term synaptic depression / cellular response to peptide hormone stimulus / protein kinase A binding / spinal cord development / neuronal cell body membrane / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / transmission of nerve impulse / AMPA glutamate receptor activity / regulation of postsynaptic membrane neurotransmitter receptor levels / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / AMPA glutamate receptor complex / adenylate cyclase binding / kainate selective glutamate receptor activity / cellular response to organic cyclic compound / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / cellular response to glycine / excitatory synapse / calcium channel regulator activity / asymmetric synapse / G-protein alpha-subunit binding / regulation of receptor recycling / voltage-gated calcium channel activity / neuronal action potential / Unblocking of NMDA receptors, glutamate binding and activation / regulation of postsynaptic membrane potential / postsynaptic density, intracellular component / glutamate receptor binding / positive regulation of synaptic transmission / long-term memory / response to electrical stimulus / glutamate-gated receptor activity / presynaptic active zone membrane / beta-2 adrenergic receptor binding / response to fungicide / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / dendrite membrane / synapse assembly / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cytoskeletal protein binding / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / positive regulation of synaptic transmission, glutamatergic / SNARE binding / response to cocaine / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / PDZ domain binding / long-term synaptic potentiation / protein tetramerization / cellular response to amino acid stimulus / postsynaptic density membrane / ionotropic glutamate receptor binding / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / regulation of synaptic plasticity / establishment of protein localization / neuromuscular junction / response to organic cyclic compound / receptor internalization / terminal bouton / recycling endosome / response to toxic substance / cerebral cortex development / cellular response to growth factor stimulus Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | ||||||||||||
![]() | Zhang, D. / Lape, R. / Shaikh, S. / Kohegyi, B. / Watson, J.F. / Cais, O. / Nakagawa, T. / Greger, I. | ||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. Authors: Danyang Zhang / Remigijus Lape / Saher A Shaikh / Bianka K Kohegyi / Jake F Watson / Ondrej Cais / Terunaga Nakagawa / Ingo H Greger / ![]() ![]() ![]() Abstract: AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an ...AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators. | ||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 703.7 KB | Display | ![]() |
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PDB format | ![]() | 559.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.9 MB | Display | ![]() |
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Full document | ![]() | 1.9 MB | Display | |
Data in XML | ![]() | 79.8 KB | Display | |
Data in CIF | ![]() | 107.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 15714MC ![]() 8aymC ![]() 8aynC ![]() 8ayoC 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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Noncrystallographic symmetry (NCS) | NCS domain:
NCS domain segments:
NCS oper: (Code: givenMatrix: (-0.999999534776, 0.000280959879172, 0.000922772238202), (-0.000281262083838, -0.999999906856, -0.000327383046606), (0.00092268017075, -0.000327642435143, 0.999999520656) ...NCS oper: (Code: given Matrix: (-0.999999534776, 0.000280959879172, 0.000922772238202), Vector: |
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Components
-Isoform Flip of Glutamate receptor ... , 2 types, 4 molecules BDAC
#1: Protein | Mass: 96247.055 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Protein | Mass: 102661.930 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Protein , 1 types, 2 molecules JI
#2: Protein | Mass: 43576.004 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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-Non-polymers , 5 types, 24 molecules ![](data/chem/img/ZK1.gif)
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![](data/chem/img/PLM.gif)
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![](data/chem/img/OLC.gif)
![](data/chem/img/PLM.gif)
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#4: Chemical | ChemComp-ZK1 / {[ #5: Chemical | ChemComp-OLC / ( #6: Chemical | ChemComp-PLM / #7: Chemical | ChemComp-POV / ( #8: Chemical | |
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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: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059 Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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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: 3000 nm / Nominal defocus min: 1200 nm |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 315406 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 51.41 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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Refine LS restraints NCS | Type: NCS constraints / Rms dev position: 0.00069860284038 Å |