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- EMDB-15718: Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 an... -
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Open data
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Basic information
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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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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 / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() ![]() | ||||||||||||
Method | ![]() ![]() | ||||||||||||
![]() | Zhang D / Lape R / Shaikh S / Kohegyi B / Watson JF / Cais O / Nakagawa T / Greger IH | ||||||||||||
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
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 12.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.1 KB 22.1 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.4 KB | Display | ![]() |
Images | ![]() | 129.4 KB | ||
Others | ![]() ![]() ![]() | 4.9 MB 97 MB 97 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ayoMC ![]() 8aylC ![]() 8aymC ![]() 8aynC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
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
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Density Histograms |
-Half map: #1
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-Half map: #2
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Density Histograms |
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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
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
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 |