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Yorodumi- EMDB-40748: Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxil... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40748 | |||||||||||||||
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Title | Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state) | |||||||||||||||
Map data | Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state) | |||||||||||||||
Sample |
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Keywords | AMPA receptor / neurotransmission / TARP gamma-5 / perampanel / SIGNALING PROTEIN | |||||||||||||||
Function / homology | Function and homology information neurotransmitter receptor transport, postsynaptic endosome to lysosome / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / postsynaptic neurotransmitter receptor diffusion trapping / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space ...neurotransmitter receptor transport, postsynaptic endosome to lysosome / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / postsynaptic neurotransmitter receptor diffusion trapping / 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 / 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 / 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 / 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 | Rattus norvegicus (Norway rat) | |||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.72 Å | |||||||||||||||
Authors | Gangwar SP / Yen LY / Yelshanskaya MV / Sobolevsky AI | |||||||||||||||
Funding support | United States, 4 items
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Citation | Journal: Nat Struct Mol Biol / Year: 2023 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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40748.map.gz | 259.1 MB | EMDB map data format | |
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Header (meta data) | emd-40748-v30.xml emd-40748.xml | 22.4 KB 22.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40748_fsc.xml | 13.7 KB | Display | FSC data file |
Images | emd_40748.png | 74.4 KB | ||
Filedesc metadata | emd-40748.cif.gz | 7.3 KB | ||
Others | emd_40748_half_map_1.map.gz emd_40748_half_map_2.map.gz | 255 MB 255 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40748 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40748 | HTTPS FTP |
-Validation report
Summary document | emd_40748_validation.pdf.gz | 773.5 KB | Display | EMDB validaton report |
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Full document | emd_40748_full_validation.pdf.gz | 773 KB | Display | |
Data in XML | emd_40748_validation.xml.gz | 22.9 KB | Display | |
Data in CIF | emd_40748_validation.cif.gz | 29.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40748 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40748 | HTTPS FTP |
-Related structure data
Related structure data | 8ss9MC 8bhfC 8ss2C 8ss3C 8ss4C 8ss5C 8ss6C 8ss7C 8ss8C 8ssaC 8ssbC C: citing same article (ref.) M: atomic model generated by this map |
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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_40748.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state) | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.925 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_40748_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_40748_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : GluA2-TARP gamma5
Entire | Name: GluA2-TARP gamma5 |
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Components |
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-Supramolecule #1: GluA2-TARP gamma5
Supramolecule | Name: GluA2-TARP gamma5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 Details: LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 bound to competitive antagonist ZK and antiepileptic drug perampanel (closed state) |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
-Macromolecule #1: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 s...
Macromolecule | Name: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 114.978859 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY ...String: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY RSLFQDLELK KERRVILDCE RDKVNDIVDQ VITIGKHVKG YHYIIANLGF TDGDLLKIQF GGAEVSGFQI VD YDDSLVS KFIERWSTLE EKEYPGAHTA TIKYTSALTY DAVQVMTEAF RNLRKQRIEI SRRGNAGDCL ANPAVPWGQG VEI ERALKQ VQVEGLSGNI KFDQNGKRIN YTINIMELKT NGPRKIGYWS EVDKMVLTED DTSGLEQKTV VVTTILESPY VMMK KNHEM LEGNERYEGY CVDLAAEIAK HCGFKYKLTI VGDGKYGARD ADTKIWNGMV GELVYGKADI AIAPLTITLV REEVI DFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVVLFLV SRFSPYEWHT EEFEDGRETQ SSESTN EFG IFNSLWFSLG AFMQQGCDIS PRSLSGRIVG GVWWFFTLII ISSYTANLAA FLTVERMVSP IESAEDLSKQ TEIAYGT LD SGSTKEFFRR SKIAVFDKMW TYMRSAEPSV FVRTTAEGVA RVRKSKGKYA YLLESTMNEY IEQRKPCDTM KVGGNLDS K GYGIATPKGS SLGTPVNLAV LKLSEQGVLD KLKNKWWYDK GECGAKDSGS KEKTSALSLS NVAGVFYILV GGLGLAMLV ALIEFCYKSR AEAKRMKGTG SACGRKALTL LSSVFAVCGL GLLGIAVSTD YWLYLEEGII LPQNQSTEVK MSLHSGLWRV CFLAGEERG RCFTIEYVMP MNSQMTSEST VNVLKMIRSA TPFPLVSLFF MFIGFILSNI GHIRPHRTIL AFVSGIFFIL S GLSLVVGL VLYISSINDE MLNRTKDAET YFNYKYGWSF AFAAISFLLT ESAGVMSVYL FMKRYTAE UniProtKB: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit |
-Macromolecule #2: 2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile
Macromolecule | Name: 2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile type: ligand / ID: 2 / Number of copies: 4 / Formula: 6ZP |
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Molecular weight | Theoretical: 349.385 Da |
Chemical component information | ChemComp-6ZP: |
-Macromolecule #3: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquino...
Macromolecule | Name: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid type: ligand / ID: 3 / Number of copies: 4 / Formula: ZK1 |
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Molecular weight | Theoretical: 409.254 Da |
Chemical component information | ChemComp-ZK1: |
-Macromolecule #4: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 14 / Formula: PCW |
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Molecular weight | Theoretical: 787.121 Da |
Chemical component information | ChemComp-PCW: |
-Macromolecule #5: CHOLESTEROL
Macromolecule | Name: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 2 / Formula: CLR |
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Molecular weight | Theoretical: 386.654 Da |
Chemical component information | ChemComp-CLR: |
-Macromolecule #6: SODIUM ION
Macromolecule | Name: SODIUM ION / type: ligand / ID: 6 / Number of copies: 2 |
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Molecular weight | Theoretical: 22.99 Da |
-Macromolecule #7: water
Macromolecule | Name: water / type: ligand / ID: 7 / Number of copies: 15 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4.5 mg/mL | |||||||||||||||
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Buffer | pH: 8 Component:
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Grid | Model: UltrAuFoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR | |||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: vitrification carried out in nitrogen atmosphere. | |||||||||||||||
Details | Protein extracted and purified in detergent micelle. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |