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- EMDB-40741: Structure of AMPA receptor GluA2 complex with auxiliary subunits ... -

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Entry
Database: EMDB / ID: EMD-40741
TitleStructure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
Map dataStructure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
Sample
  • Complex: GluA2-TARP gamma5-cornichon-2
    • Protein or peptide: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera
    • Protein or peptide: Protein cornichon homolog 2
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: Digitonin
  • Ligand: SPERMIDINE
KeywordsAMPA receptor / spermidine / TARP gamma-5 / cornichon-2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


postsynaptic neurotransmitter receptor diffusion trapping / channel regulator activity / Cargo concentration in the ER / regulation of AMPA receptor activity / COPII-mediated vesicle transport / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space ...postsynaptic neurotransmitter receptor diffusion trapping / channel regulator activity / Cargo concentration in the ER / regulation of AMPA receptor activity / COPII-mediated vesicle transport / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / transmission of nerve impulse / ligand-gated monoatomic cation channel activity / 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 / cellular response to glycine / extracellularly glutamate-gated ion channel activity / asymmetric synapse / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / positive regulation of synaptic transmission / voltage-gated calcium channel activity / glutamate-gated receptor activity / regulation of synaptic transmission, glutamatergic / response to fungicide / cytoskeletal protein binding / vesicle-mediated transport / ionotropic glutamate receptor binding / extracellular ligand-gated monoatomic ion channel activity / presynaptic active zone membrane / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / glutamate-gated calcium ion channel activity / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite cytoplasm / dendrite membrane / endoplasmic reticulum-Golgi intermediate compartment membrane / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / SNARE binding / dendritic shaft / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / establishment of protein localization / synaptic membrane / ER to Golgi transport vesicle membrane / modulation of chemical synaptic transmission / postsynaptic density membrane / terminal bouton / Schaffer collateral - CA1 synapse / cerebral cortex development / receptor internalization / synaptic vesicle membrane / synaptic vesicle / signaling receptor activity / presynapse / amyloid-beta binding / presynaptic membrane / growth cone / scaffold protein binding / chemical synaptic transmission / dendritic spine / perikaryon / postsynaptic membrane / neuron projection / postsynaptic density / axon / signaling receptor binding / neuronal cell body / synapse / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / protein kinase binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, gamma-5 subunit / Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / PMP-22/EMP/MP20/Claudin tight junction / : / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily ...Voltage-dependent calcium channel, gamma-5 subunit / Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / PMP-22/EMP/MP20/Claudin tight junction / : / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / 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 / Protein cornichon homolog 2 / Voltage-dependent calcium channel gamma-5 subunit
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.58 Å
AuthorsGangwar SP / Yen LY / 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)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
National Institutes of Health/National Cancer Institute (NIH/NCI)CA206573 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-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40741.png

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Map

FileDownload / File: emd_40741.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationStructure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 416 pix.
= 345.28 Å		0.83 Å/pix.
x 416 pix.
= 345.28 Å		0.83 Å/pix.
x 416 pix.
= 345.28 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-0.71756285 - 1.1065997
Average (Standard dev.)0.0016285527 (±0.025300965)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 345.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40741_half_map_1.map
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Half map: #1

Fileemd_40741_half_map_2.map
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Sample components

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Entire : GluA2-TARP gamma5-cornichon-2

EntireName: GluA2-TARP gamma5-cornichon-2
Components
  • Complex: GluA2-TARP gamma5-cornichon-2
    • Protein or peptide: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera
    • Protein or peptide: Protein cornichon homolog 2
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: Digitonin
  • Ligand: SPERMIDINE

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Supramolecule #1: GluA2-TARP gamma5-cornichon-2

SupramoleculeName: GluA2-TARP gamma5-cornichon-2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed 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: Protein cornichon homolog 2

MacromoleculeName: Protein cornichon homolog 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.94842 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MAFTFAAFCY MLTLVLCASL IFFVIWHIIA FDELRTDFKN PIDQGNPARA RERLKNIERI CCLLRKLVVP EYSIHGLFCL MFLCAAEWV TLGLNIPLLF YHLWRYFHRP ADGSEVMYDA VSIMNADILN YCQKESWCKL AFYLLSFFYY LYSMVYTLVS F

UniProtKB: Protein cornichon homolog 2

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Macromolecule #3: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquino...

MacromoleculeName: {[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
Molecular weightTheoretical: 409.254 Da
Chemical component information

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / antagonist, medication*YM

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Macromolecule #4: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 26 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: Digitonin

MacromoleculeName: Digitonin / type: ligand / ID: 6 / Number of copies: 2 / Formula: AJP
Molecular weightTheoretical: 1.229312 KDa
Chemical component information

ChemComp-AJP:
Digitonin / detergent*YM

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Macromolecule #7: SPERMIDINE

MacromoleculeName: SPERMIDINE / type: ligand / ID: 7 / Number of copies: 1 / Formula: SPD
Molecular weightTheoretical: 145.246 Da
Chemical component information

ChemComp-SPD:
SPERMIDINE

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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 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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 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 stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
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)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0.3) / Number images used: 55275
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

SoftwareName: Coot
Output model

PDB-8ss2:
Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state)

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