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- EMDB-70925: Heteromeric GluA1/A2 in the desensitized state, composite map of ... -

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Basic information

Entry
Database: EMDB / ID: EMD-70925
TitleHeteromeric GluA1/A2 in the desensitized state, composite map of ATD-LBD-TMD
Map dataA1A2 desensitized state (composite map)
Sample
  • Complex: Heteromeric GluA1A2 with competitive antagonist ZK
    • Protein or peptide: Isoform Flip of Glutamate receptor 1
    • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
KeywordsGluA1A2 heterotetramer quisqualate iGluR / MEMBRANE PROTEIN
Function / homology
Function and homology information


Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / COPII-mediated vesicle transport / positive regulation of membrane potential / cellular response to ammonium ion / response to sucrose / myosin V binding / neuron spine / Trafficking of AMPA receptors ...Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / COPII-mediated vesicle transport / positive regulation of membrane potential / cellular response to ammonium ion / response to sucrose / myosin V binding / neuron spine / Trafficking of AMPA receptors / proximal dendrite / response to arsenic-containing substance / regulation of monoatomic ion transmembrane transport / cellular response to L-glutamate / ligand-gated calcium channel activity / cellular response to dsRNA / dendritic spine membrane / beta-2 adrenergic receptor binding / Synaptic adhesion-like molecules / long-term synaptic depression / cellular response to peptide hormone stimulus / spine synapse / dendritic spine neck / dendritic spine cytoplasm / dendritic spine head / cellular response to amine stimulus / peptide hormone receptor binding / response to psychosocial stress / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / response to morphine / perisynaptic space / spinal cord development / neuronal cell body membrane / protein kinase A binding / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / AMPA glutamate receptor activity / AMPA glutamate receptor clustering / kainate selective glutamate receptor activity / immunoglobulin binding / adenylate cyclase binding / behavioral response to pain / AMPA glutamate receptor complex / regulation of receptor recycling / response to electrical stimulus / extracellularly glutamate-gated ion channel activity / cellular response to glycine / ionotropic glutamate receptor complex / asymmetric synapse / Unblocking of NMDA receptors, glutamate binding and activation / G-protein alpha-subunit binding / conditioned place preference / glutamate receptor binding / positive regulation of synaptic transmission / long-term memory / postsynaptic density, intracellular component / regulation of synaptic transmission, glutamatergic / response to fungicide / neuronal action potential / extracellular ligand-gated monoatomic ion channel activity / cytoskeletal protein binding / glutamate-gated receptor activity / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / somatodendritic compartment / glutamate-gated calcium ion channel activity / synapse assembly / presynaptic active zone membrane / excitatory synapse / ionotropic glutamate receptor signaling pathway / ionotropic glutamate receptor binding / dendrite membrane / dendrite cytoplasm / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of excitatory postsynaptic potential / dendritic shaft / SNARE binding / synaptic membrane / PDZ domain binding / response to cocaine / neuromuscular junction / establishment of protein localization / protein tetramerization / cellular response to amino acid stimulus / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / response to nutrient levels / cerebral cortex development / regulation of synaptic plasticity / receptor internalization / recycling endosome / postsynaptic density membrane / response to peptide hormone / cellular response to growth factor stimulus / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / response to toxic substance / recycling endosome membrane / small GTPase binding
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: 4.91 Å
AuthorsYen LY / Newton TP / Gangwar SP / Sobolevsky AI
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_70925.png

Downloads & links

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Map

FileDownload / File: emd_70925.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationA1A2 desensitized state (composite map)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.33 Å/pix.
x 256 pix.
= 340.48 Å		1.33 Å/pix.
x 256 pix.
= 340.48 Å		1.33 Å/pix.
x 256 pix.
= 340.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.33 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-0.08110458 - 1.822639
Average (Standard dev.)0.012983123 (±0.044003278)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 340.48 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: Isoform Flip of Glutamate receptor 1
    • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID

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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: Isoform Flip of Glutamate receptor 1

MacromoleculeName: Isoform Flip of Glutamate receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 91.225055 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NNIQIGGLFP NQQSQEHAAF RFALSQLTEP PKLLPQIDIV NISDSFEMTY RFCSQFSKGV YAIFGFYERR TVNMLTSFCG ALHVCFITP SFPVDTSNQF VLQLRPELQE ALISIIDHYK WQTFVYIYDA DRGLSVLQRV LDTAAEKNWQ VTAVNILTTT E EGYRMLFQ ...String:
NNIQIGGLFP NQQSQEHAAF RFALSQLTEP PKLLPQIDIV NISDSFEMTY RFCSQFSKGV YAIFGFYERR TVNMLTSFCG ALHVCFITP SFPVDTSNQF VLQLRPELQE ALISIIDHYK WQTFVYIYDA DRGLSVLQRV LDTAAEKNWQ VTAVNILTTT E EGYRMLFQ DLEKKKERLV VVDCESERLN AILGQIVKLE KNGIGYHYIL ANLGFMDIDL NKFKESGANV TGFQLVNYTD TI PARIMQQ WRTSDSRDHT RVDWKRPKYT SALTYDGVKV MAEAFQSLRR QRIDISRRGN AGDCLANPAV PWGQGIDIQR ALQ QVRFEG LTGNVQFNEK GRRTNYTLHV IEMKHDGIRK IGYWNEDDKF VPAGGDNSSV QNRTYIVTTI LEDPYVMLKK NANQ FEGND RYEGYCVELA AEIAKHVGYS YRLEIVSDGK YGARDPDTKA WNGMVGELVY GRADVAVAPL TITLVREEVI DFSKP FMSL GISIMIKKPQ KSKPGVFSFL DPLAYEIWMC IVFAYIGVSV VLFLVSRFSP YEWHSEEFEE GRDQTTSDQS NEFGIF NSL WFSLGAFMQQ GCDISPRSLS GRIVGGVWWF FTLIIISSYT ANLAAFLTVE RMVSPIESAE DLAKQTEIAY GTLEAGS TK EFFRRSKIAV FEKMWTYMKS AEPSVFVRTT EEGMIRVRKS KGKYAYLLES TMNEYIEQRK PCDTMKVGGN LDSKGYGI A TPKGSALRGP VNLAVLKLSE QGVLDKLKSK WWYDKGECGS KDSGSKDKTS ALSLSNVAGV FYILIGGLGL AMLVALIEF CYKSR

UniProtKB: Glutamate receptor 1

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Macromolecule #2: Isoform Flip of Glutamate receptor 2

MacromoleculeName: Isoform Flip of Glutamate receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 91.054867 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 EEFEDGRETW SSESTN EFG IFNSLWFSLG AFMRQGCDIS 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 A

UniProtKB: Glutamate receptor 2

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Macromolecule #3: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID

MacromoleculeName: (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID
type: ligand / ID: 3 / Number of copies: 4 / Formula: QUS
Molecular weightTheoretical: 189.126 Da
Chemical component information

ChemComp-QUS:
(S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID / agonist*YM

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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
1.0 mMC5H7N3O5quiqualate

Details: 150 mM NaCl, 20 mM Tris-HCl pH 8.0, and 0.05% digitonin, 1 mM quiqualate
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 500
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 correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio from the experimental data
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.91 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 251523
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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