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- EMDB-40744: Structure of LBD-TMD of AMPA receptor GluA2 in complex with auxil... -

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Entry
Database: EMDB / ID: EMD-40744
TitleStructure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 (apo state)
Map dataStructure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 (apo state)
Sample
  • Complex: GluA2-TARP gamma5
    • Protein or peptide: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera
  • Ligand: SODIUM IONSodium
KeywordsAMPA receptor / neurotransmission / TARP gamma-5 / Ion-channel / 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 / response to lithium ion ...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 / response to lithium ion / perisynaptic space / cellular response to glycine / transmission of nerve impulse / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / immunoglobulin binding / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / asymmetric synapse / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / voltage-gated calcium channel activity / glutamate receptor binding / positive regulation of synaptic transmission / glutamate-gated receptor activity / presynaptic active zone membrane / response to fungicide / cellular response to brain-derived neurotrophic factor stimulus / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / 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 / SNARE binding / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / PDZ domain binding / postsynaptic density membrane / protein tetramerization / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / establishment of protein localization / terminal bouton / receptor internalization / synaptic vesicle membrane / cerebral cortex development / synaptic vesicle / presynapse / presynaptic membrane / signaling receptor activity / amyloid-beta binding / growth cone / perikaryon / chemical synaptic transmission / scaffold protein binding / postsynaptic membrane / dendritic spine / postsynaptic density / neuron projection / axon / neuronal cell body / dendrite / synapse / glutamatergic synapse / protein-containing complex binding / endoplasmic reticulum membrane / protein kinase binding / cell surface / endoplasmic reticulum / protein-containing complex / membrane / identical protein binding / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, gamma-5 subunit / PMP-22/EMP/MP20/Claudin tight junction / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel ...Voltage-dependent calcium channel, gamma-5 subunit / PMP-22/EMP/MP20/Claudin tight junction / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Glutamate receptor 2 / Voltage-dependent calcium channel gamma-5 subunit
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.56 Å
AuthorsYen LY / Gangwar SP / Yelshanskaya MV / Sobolevsky AI
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS107253 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)AR078814 United States
CitationJournal: 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
DepositionMay 8, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateOct 25, 2023-
Current statusOct 25, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40744.png

Downloads & links

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Map

FileDownload / File: emd_40744.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of LBD-TMD of AMPA receptor GluA2 in complex with auxiliary subunit TARP gamma-5 (apo state)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.34
Minimum - Maximum-2.7823763 - 4.2462416
Average (Standard dev.)0.0048104534 (±0.075121686)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 339.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_40744_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_40744_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GluA2-TARP gamma5

EntireName: GluA2-TARP gamma5
Components
  • Complex: GluA2-TARP gamma5
    • Protein or peptide: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera
  • Ligand: SODIUM IONSodium

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Supramolecule #1: GluA2-TARP gamma5

SupramoleculeName: 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 (apo state)
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 s...

MacromoleculeName: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 114.978859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 2 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration4.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMC4H11NO3Tris
150.0 mMNaClSodium chlorideSodium chloride
0.05 %C56H92O29Digitonin
0.005 %C31H50O4Cholesteryl hemisuccinate
GridModel: UltrAuFoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: vitrification carried out in nitrogen atmosphere.
DetailsProtein extracted and purified in detergent micelle.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Initial model generated from the data (ab initio)
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.56 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0.3) / Number images used: 81879
FSC plot (resolution estimation)

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