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Yorodumi- EMDB-15718: Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 an... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15718 | ||||||||||||
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Title | Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059 | ||||||||||||
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Sample |
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Function / homology | Function and homology information 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 / chemical synaptic transmission, postsynaptic / cellular response to ammonium ion / neurotransmitter receptor transport, postsynaptic endosome to lysosome ...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 / chemical synaptic transmission, postsynaptic / 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 / Trafficking of AMPA receptors / myosin V binding / neuron spine / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / protein phosphatase 2B binding / response to arsenic-containing substance / postsynaptic neurotransmitter receptor diffusion trapping / cellular response to dsRNA / dendritic spine membrane / Synaptic adhesion-like molecules / long-term synaptic depression / beta-2 adrenergic receptor binding / cellular response to peptide hormone stimulus / protein kinase A binding / neuronal cell body membrane / spinal cord development / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / response to lithium ion / perisynaptic space / cellular response to glycine / transmission of nerve impulse / AMPA glutamate receptor activity / regulation of postsynaptic membrane neurotransmitter receptor levels / Trafficking of GluR2-containing AMPA receptors / immunoglobulin binding / calcium channel regulator activity / neuronal action potential / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / excitatory synapse / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / adenylate cyclase binding / cellular response to organic cyclic compound / asymmetric synapse / G-protein alpha-subunit binding / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / voltage-gated calcium channel activity / glutamate receptor binding / regulation of postsynaptic membrane potential / long-term memory / positive regulation of synaptic transmission / response to electrical stimulus / glutamate-gated receptor activity / presynaptic active zone membrane / response to fungicide / regulation of synaptic transmission, glutamatergic / cellular response to brain-derived neurotrophic factor stimulus / somatodendritic compartment / synapse assembly / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor binding / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / cytoskeletal protein binding / positive regulation of synaptic transmission, glutamatergic / monoatomic ion transmembrane transport / SNARE binding / response to cocaine / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / PDZ domain binding / cellular response to amino acid stimulus / postsynaptic density membrane / protein tetramerization / regulation of synaptic plasticity / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / neuromuscular junction / establishment of protein localization / terminal bouton / receptor internalization / response to organic cyclic compound / synaptic vesicle membrane / cerebral cortex development / response to toxic substance / recycling endosome / response to peptide hormone Similarity search - Function | ||||||||||||
Biological species | Rattus norvegicus (Norway rat) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||
Authors | Zhang D / Lape R / Shaikh S / Kohegyi B / Watson JF / Cais O / Nakagawa T / Greger IH | ||||||||||||
Funding support | United Kingdom, United States, 3 items
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Citation | Journal: Nat Commun / Year: 2023 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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_15718.map.gz | 12.8 MB | EMDB map data format | |
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Header (meta data) | emd-15718-v30.xml emd-15718.xml | 22.1 KB 22.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_15718_fsc.xml | 11.4 KB | Display | FSC data file |
Images | emd_15718.png | 129.4 KB | ||
Others | emd_15718_additional_1.map.gz emd_15718_half_map_1.map.gz emd_15718_half_map_2.map.gz | 4.9 MB 97 MB 97 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15718 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15718 | HTTPS FTP |
-Related structure data
Related structure data | 8ayoMC 8aylC 8aymC 8aynC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_15718.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_15718_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_15718_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_15718_half_map_2.map | ||||||||||||
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Density Histograms |
-Sample components
+Entire : GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JN...
+Supramolecule #1: GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JN...
+Macromolecule #1: Isoform Flip of Glutamate receptor 1
+Macromolecule #2: Isoform Flip of Glutamate receptor 2
+Macromolecule #3: Voltage-dependent calcium channel gamma-8 subunit
+Macromolecule #4: GLUTAMIC ACID
+Macromolecule #5: CYCLOTHIAZIDE
+Macromolecule #6: (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
+Macromolecule #7: PALMITIC ACID
+Macromolecule #8: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...
+Macromolecule #9: 5-[2-(4-fluorophenyl)-7-(4-oxidanylpiperidin-1-yl)pyrazolo[1,5-c]...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |