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- EMDB-70912: Heteromeric GluA1/A2 in the inactive state, composite map of LBD-TMD -

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Basic information

Entry
Database: EMDB / ID: EMD-70912
TitleHeteromeric GluA1/A2 in the inactive state, composite map of LBD-TMD
Map datacomposite map of A1A2 ZK (LBD-TMD)
Sample
  • Complex: Heteromeric GluA1A2 with competitive antagonist ZK
    • Protein or peptide: Glutamate receptor 1
    • Protein or peptide: Glutamate receptor 2
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
  • Ligand: SODIUM ION
  • Ligand: water
KeywordsGluA1A2 heterotetramer ZK iGluR / MEMBRANE PROTEIN
Function / homology
Function and homology information


Cargo concentration in the ER / axonal spine / cellular response to ammonium ion / COPII-mediated vesicle transport / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / response to sucrose / regulation of monoatomic ion transmembrane transport / cellular response to L-glutamate / myosin V binding ...Cargo concentration in the ER / axonal spine / cellular response to ammonium ion / COPII-mediated vesicle transport / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / response to sucrose / regulation of monoatomic ion transmembrane transport / cellular response to L-glutamate / myosin V binding / neuron spine / Trafficking of AMPA receptors / proximal dendrite / response to arsenic-containing substance / cellular response to dsRNA / long-term synaptic depression / ligand-gated calcium channel activity / dendritic spine membrane / beta-2 adrenergic receptor binding / Synaptic adhesion-like molecules / cellular response to peptide hormone stimulus / spinal cord development / regulation of synaptic plasticity by chemical substance / spine synapse / dendritic spine neck / dendritic spine cytoplasm / cellular response to amine stimulus / response to phorbol 13-acetate 12-myristate / dendritic spine head / response to psychosocial stress / peptide hormone receptor binding / response to morphine / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / perisynaptic space / behavioral response to pain / neuronal cell body membrane / response to lithium ion / Trafficking of GluR2-containing AMPA receptors / protein kinase A binding / AMPA glutamate receptor activity / AMPA glutamate receptor clustering / regulation of receptor recycling / neuronal action potential / kainate selective glutamate receptor activity / response to electrical stimulus / adenylate cyclase binding / AMPA glutamate receptor complex / extracellularly glutamate-gated ion channel activity / ionotropic glutamate receptor complex / cellular response to glycine / immunoglobulin binding / asymmetric synapse / Unblocking of NMDA receptors, glutamate binding and activation / response to fungicide / G-protein alpha-subunit binding / glutamate receptor binding / positive regulation of synaptic transmission / long-term memory / conditioned place preference / regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / cytoskeletal protein binding / extracellular ligand-gated monoatomic ion channel activity / glutamate-gated receptor activity / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / synapse assembly / glutamate-gated calcium ion channel activity / somatodendritic compartment / presynaptic active zone membrane / ionotropic glutamate receptor binding / excitatory synapse / ionotropic glutamate receptor signaling pathway / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite cytoplasm / dendrite membrane / cellular response to amino acid stimulus / response to cocaine / positive regulation of excitatory postsynaptic potential / SNARE binding / establishment of protein localization / synaptic membrane / neuromuscular junction / synaptic transmission, glutamatergic / PDZ domain binding / cerebral cortex development / response to toxic substance / dendritic shaft / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / protein tetramerization / long-term synaptic potentiation / receptor internalization / response to nutrient levels / regulation of synaptic plasticity / recycling endosome / cellular response to growth factor stimulus / postsynaptic density membrane / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission
Similarity search - Function
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 1 / Glutamate receptor 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsYen LY / Sobolevsky AI / Newton TP / Gangwar SP
Funding support United States, 9 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM129539 United States
Simons FoundationSF349247 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM129541 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS132554 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS139087 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
National Institutes of Health/National Cancer Institute (NIH/NCI)CA206573 United States
CitationJournal: Nat Commun / Year: 2026
Title: Auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric GluA1/A2 AMPA receptor core.
Authors: Laura Y Yen / Thomas P Newton / Maria V Yelshanskaya / Muhammed Aktolun / Shanti Pal Gangwar / Rasmus P Clausen / Maria G Kurnikova / Alexander I Sobolevsky /
Abstract: AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate the fast component of excitatory neurotransmission. They govern synaptic plasticity that underlies learning and memory, while their ...AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate the fast component of excitatory neurotransmission. They govern synaptic plasticity that underlies learning and memory, while their dysregulation is implicated in numerous neurological disorders. The functional diversity of AMPARs arises from variations in their subunit composition and also their association with auxiliary subunits. While multiple structures of homomeric AMPARs have been reported, structural information for the heteromeric core - particularly in the absence of auxiliary subunits, which would serve as a functional and structural baseline - has been limited. Here, we report cryo-electron microscopy structures of GluA1/A2, the most abundant AMPAR di-heteromer in the brain, in the closed, open, and desensitized states. Using molecular dynamics (MD) simulations and cross-correlating structural and functional information, we find that auxiliary subunits increase the diameter of channel pore, which corresponds to larger conductance. Likewise, we find that recovery from desensitization slows with greater disruption of two-fold rotational symmetry of the ligand-binding domain dimer in the desensitized state. Both receptor activation and desensitization vary with the type and number of associated auxiliary proteins. These structures offer a foundation for uncovering how auxiliary subunits reshape structural asymmetry and functional plasticity in heterotetrameric AMPARs.
History
DepositionMay 31, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateMay 20, 2026-
Current statusMay 20, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70912.png

Downloads & links

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Map

FileDownload / File: emd_70912.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcomposite map of A1A2 ZK (LBD-TMD)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 448 pix.
= 370.048 Å		0.83 Å/pix.
x 448 pix.
= 370.048 Å		0.83 Å/pix.
x 448 pix.
= 370.048 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-40.900463000000002 - 68.442300000000003
Average (Standard dev.)-0.0028541905 (±0.9564177)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 370.04797 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Heteromeric GluA1A2 with competitive antagonist ZK

EntireName: Heteromeric GluA1A2 with competitive antagonist ZK
Components
  • Complex: Heteromeric GluA1A2 with competitive antagonist ZK
    • Protein or peptide: Glutamate receptor 1
    • Protein or peptide: Glutamate receptor 2
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
  • Ligand: SODIUM ION
  • Ligand: water

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Supramolecule #1: Heteromeric GluA1A2 with competitive antagonist ZK

SupramoleculeName: Heteromeric GluA1A2 with competitive antagonist ZK / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 556 KDa

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Macromolecule #1: Glutamate receptor 1

MacromoleculeName: Glutamate receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 48.183172 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SVQNRTYIVT TILEDPYVML KKNANQFEGN DRYEGYCVEL AAEIAKHVGY SYRLEIVSDG KYGARDPDTK AWNGMVGELV YGRADVAVA PLTITLVREE VIDFSKPFMS LGISIMIKKP QKSKPGVFSF LDPLAYEIWM CIVFAYIGVS VVLFLVSRFS P YEWHSEEF ...String:
SVQNRTYIVT TILEDPYVML KKNANQFEGN DRYEGYCVEL AAEIAKHVGY SYRLEIVSDG KYGARDPDTK AWNGMVGELV YGRADVAVA PLTITLVREE VIDFSKPFMS LGISIMIKKP QKSKPGVFSF LDPLAYEIWM CIVFAYIGVS VVLFLVSRFS P YEWHSEEF EEGRDQTTSD QSNEFGIFNS LWFSLGAFMQ QGCDISPRSL SGRIVGGVWW FFTLIIISSY TANLAAFLTV ER MVSPIES AEDLAKQTEI AYGTLEAGST KEFFRRSKIA VFEKMWTYMK SAEPSVFVRT TEEGMIRVRK SKGKYAYLLE STM NEYIEQ RKPCDTMKVG GNLDSKGYGI ATPKGSALRG PVNLAVLKLS EQGVLDKLKS KWWYDKGECG SGGGDSKDKT SALS LSNVA GVFYILIGGL GLAMLVALIE FCYKSR

UniProtKB: Glutamate receptor 1

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Macromolecule #2: Glutamate receptor 2

MacromoleculeName: Glutamate receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 47.751934 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QKTVVVTTIL ESPYVMMKKN HEMLEGNERY EGYCVDLAAE IAKHCGFKYK LTIVGDGKYG ARDADTKIWN GMVGELVYGK ADIAIAPLT ITLVREEVID FSKPFMSLGI SIMIKKPQKS KPGVFSFLDP LAYEIWMCIV FAYIGVSVVL FLVSRFSPYE W HTEEFEDG ...String:
QKTVVVTTIL ESPYVMMKKN HEMLEGNERY EGYCVDLAAE IAKHCGFKYK LTIVGDGKYG ARDADTKIWN GMVGELVYGK ADIAIAPLT ITLVREEVID FSKPFMSLGI SIMIKKPQKS KPGVFSFLDP LAYEIWMCIV FAYIGVSVVL FLVSRFSPYE W HTEEFEDG RETQSSESTN EFGIFNSLWF SLGAFMRQGC DISPRSLSGR IVGGVWWFFT LIIISSYTAN LAAFLTVERM VS PIESAED LSKQTEIAYG TLDSGSTKEF FRRSKIAVFD KMWTYMRSAE PSVFVRTTAE GVARVRKSKG KYAYLLESTM NEY IEQRKP CDTMKVGGNL DSKGYGIATP KGSSLGTPVN LAVLKLSEQG VLDKLKNKWW YDKGECGSGG GDSKEKTSAL SLSN VAGVF YILVGGLGLA MLVALIEFCY KSRA

UniProtKB: Glutamate receptor 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 / medication*YM

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 3
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 8 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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
150.0 mMNaClsodium chloride
20.0 mMC4H11NO3Tris-HCl (pH 8.0)
0.05 %C56H92O29digitonin
100.0 uMC14H15N3O6F3PZK-200775

Details: 150 mM NaCl, 20 mM Tris-HCl pH 8.0, and 0.05% digitonin, 100 uM ZK-200775
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 500 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR / Details: 15 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV
DetailsThe sample had compositional heterogeneity, with broken particles seen throughout. Otherwise, sample was monodisperse

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 45.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5527903
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio from the experimental data
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC
Details: this is a composite map; where required, consensus refinement parameters are entered
Number images used: 216104
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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