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- EMDB-75274: Heteromeric GluA1/A2 in the activated state, amino-terminal domai... -

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Basic information

Entry
Database: EMDB / ID: EMD-75274
TitleHeteromeric GluA1/A2 in the activated state, amino-terminal domain (ATD)
Map dataGluA1A2 rr2b glu (ATD only chain A/B, local refinement)
Sample
  • Complex: Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b and agonist glutamate (Glu)
    • Protein or peptide: GluA1
    • Protein or peptide: GluA2
KeywordsGluA1A2 heterotetramer active iGluR / MEMBRANE PROTEIN
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.94 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
DepositionJan 27, 2026-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75274.png

Downloads & links

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Map

FileDownload / File: emd_75274.map.gz / Format: CCP4 / Size: 281.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGluA1A2 rr2b glu (ATD only chain A/B, local refinement)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 420 pix.
= 348.6 Å		0.83 Å/pix.
x 418 pix.
= 346.94 Å		0.83 Å/pix.
x 420 pix.
= 348.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.035
Minimum - Maximum-0.30133903 - 0.36320892
Average (Standard dev.)0.00032657772 (±0.0057023163)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-1-2-2
Dimensions418420420
Spacing420418420
CellA: 348.6 Å / B: 346.94003 Å / C: 348.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: GluA1A2 rr2b glu (ATD only chain A/B, local refinement, half map A)

Fileemd_75274_half_map_1.map
AnnotationGluA1A2 rr2b glu (ATD only chain A/B, local refinement, half map A)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: GluA1A2 rr2b glu (ATD only chain A/B, local refinement, half map B)

Fileemd_75274_half_map_2.map
AnnotationGluA1A2 rr2b glu (ATD only chain A/B, local refinement, half map B)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b a...

EntireName: Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b and agonist glutamate (Glu)
Components
  • Complex: Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b and agonist glutamate (Glu)
    • Protein or peptide: GluA1
    • Protein or peptide: GluA2

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Supramolecule #1: Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b a...

SupramoleculeName: Heteromeric GluA1A2 with positive allosteric modulator (R,R)-2b and agonist glutamate (Glu)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 556 KDa

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Macromolecule #1: GluA1

MacromoleculeName: GluA1 / type: protein_or_peptide / ID: 1 / Details: GluA1, chain A/C / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FPNNIQIGGL FPNQQSQEHA AFRFALSQLT EPPKLLPQID IVNISDSFEM TYRFCSQFSK GVYAIFGFYE RRTVNMLTSF CGALHVCFIT PSFPVDTSNQ FVLQLRPELQ EALISIIDHY KWQTFVYIYD ADRGLSVLQR VLDTAAEKNW QVTAVNILTT TEEGYRMLFQ ...String:
FPNNIQIGGL FPNQQSQEHA AFRFALSQLT EPPKLLPQID IVNISDSFEM TYRFCSQFSK GVYAIFGFYE RRTVNMLTSF CGALHVCFIT PSFPVDTSNQ FVLQLRPELQ EALISIIDHY KWQTFVYIYD ADRGLSVLQR VLDTAAEKNW QVTAVNILTT TEEGYRMLFQ DLEKKKERLV VVDCESERLN AILGQIVKLE KNGIGYHYIL ANLGFMDIDL NKFKESGANV TGFQLVNYTD TIPARIMQQW RTSDSRDHTR VDWKRPKYTS ALTYDGVKVM AEAFQSLRRQ RIDISRRGNA GDCLANPAVP WGQGIDIQRA LQQVRFEGLT GNVQFNEKGR RTNYTLHVIE MKHDGIRKIG YWNEDDKFVP AGGDNSSVQN RTYIVTTILE DPYVMLKKNA NQFEGNDRYE GYCVELAAEI AKHVGYSYRL EIVSDGKYGA RDPDTKAWNG MVGELVYGRA DVAVAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFSGIFNS LWFSLGAFMQ QGCDISPRSL SGRIVGGVWW FFTLIIISSY TANLAAFLTV ERMVSPIESA EDLAKQTEIA YGTLEAGSTK EFFRRSKIAV FEKMWTYMKS AEPSVFVRTT EEGMIRVRKS KGKYAYLLES TMNEYIEQRK PCDTMKVGGN LDSKGYGIAT PKGSALRGPV NLAVLKLSEQ GVLDKLKSKW WYDKGECGKT SALSLSNVAG VFYILIGGLG LAMLVALIEF CYKSR

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Macromolecule #2: GluA2

MacromoleculeName: GluA2 / type: protein_or_peptide / ID: 2 / Details: GluA2, chain B/D / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFITP SFPTDGTHPF VIQMRPDLKG ALLSLIEYYQ WDKFAYLYDS DRGLSTLQAV LDSAAEKKWQ VTAINVGNIN NDKKDETYRS ...String:
NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFITP SFPTDGTHPF VIQMRPDLKG ALLSLIEYYQ WDKFAYLYDS DRGLSTLQAV LDSAAEKKWQ VTAINVGNIN NDKKDETYRS LFQDLELKKE RRVILDCERD KVNDIVDQVI TIGKHVKGYH YIIANLGFTD GDLLKIQFGG AEVSGFQIVD YDDSLVSKFI ERWSTLEEKE YPGAHTATIK YTSALTYDAV QVMTEAFRNL RKQRIEISRR GNAGDCLANP AVPWGQGVEI ERALKQVQVE GLSGNIKFDQ NGKRINYTIN IMELKTNGPR KIGYWSEVDK MVLTEDDTSG LEQKTVVVTT ILESPYVMMK KNHEMLEGNE RYEGYCVDLA AEIAKHCGFK YKLTIVGDGK YGARDADTKI WNGMVGELVY GKADIAIAPL TITLVREEVI DFSKPFMSLG ISIMIKKPQK SKPGVFSFLD PLAYEIWMCI VFAYIGVSVV LFLVSRFSPE FGIFNSLWFS LGAFMRQGCD ISPRSLSGRI VGGVWWFFTL IIISSYTANL AAFLTVERMV SPIESAEDLS KQTEIAYGTL DSGSTKEFFR RSKIAVFDKM WTYMRSAEPS VFVRTTAEGV ARVRKSKGKY AYLLESTMNE YIEQRKPCDT MKVGGNLDSK GYGIATPKGS SLGTPVNLAV LKLSEQGVLD KLKNKWWYDK GECGTSALSL SNVAGVFYIL VGGLGLAMLV ALIEFCYKSR

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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
0.05 %C56H92O29digitonin
500.0 uMC14H14N2O2(R,R)-2b
1.0 mMC5H9NO4glutamate

Details: 150 mM NaCl, 20 mM Tris-HCl pH 8.0, and 0.05% digitonin, 500 uM (R,R)-2b, 1 mM glutamate
GridModel: UltrAuFoil R1.2/1.3 / 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: 47.03 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: 5802290
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: initial model from the experimental data
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.94 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 121113
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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