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- EMDB-70920: Heteromeric GluA1/A2-CNIH1 in the activated state, composite map ... -

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Basic information

Entry
Database: EMDB / ID: EMD-70920
TitleHeteromeric GluA1/A2-CNIH1 in the activated state, composite map of LBD-TMD
Map dataGluA1A2-CNIH1 rr2b glu (composite map, LBD-TMD)
Sample
  • Complex: Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)
    • Protein or peptide: Isoform Flip of Glutamate receptor 1
    • Protein or peptide: Isoform Flip of Glutamate receptor 2
    • Protein or peptide: Protein cornichon homolog 1
  • Ligand: GLUTAMIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: N,N'-[biphenyl-4,4'-diyldi(2R)propane-2,1-diyl]dipropane-2-sulfonamide
  • Ligand: SODIUM ION
KeywordsGluA1A2-CNIH2 heterotetramer active iGluR / MEMBRANE PROTEIN
Function / homology
Function and homology information


Cargo concentration in the ER / cellular response to ammonium ion / axonal spine / positive regulation of locomotion involved in locomotory behavior / COPII-mediated vesicle transport / positive regulation of membrane potential / response to sucrose / regulation of monoatomic ion transmembrane transport / myosin V binding / neuron spine ...Cargo concentration in the ER / cellular response to ammonium ion / axonal spine / positive regulation of locomotion involved in locomotory behavior / COPII-mediated vesicle transport / positive regulation of membrane potential / response to sucrose / regulation of monoatomic ion transmembrane transport / myosin V binding / neuron spine / Trafficking of AMPA receptors / proximal dendrite / Cargo concentration in the ER / response to arsenic-containing substance / cellular response to L-glutamate / cellular response to dsRNA / long-term synaptic depression / ligand-gated calcium channel activity / COPII-mediated vesicle transport / dendritic spine membrane / beta-2 adrenergic receptor binding / Synaptic adhesion-like molecules / cellular response to peptide hormone stimulus / spine synapse / dendritic spine neck / dendritic spine cytoplasm / dendritic spine head / cellular response to amine stimulus / response to morphine / peptide hormone receptor binding / response to psychosocial stress / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / perisynaptic space / spinal cord development / neuronal cell body membrane / Trafficking of GluR2-containing AMPA receptors / protein kinase A binding / response to lithium ion / AMPA glutamate receptor activity / AMPA glutamate receptor clustering / regulation of receptor recycling / kainate selective glutamate receptor activity / behavioral response to pain / immunoglobulin binding / adenylate cyclase binding / AMPA glutamate receptor complex / extracellularly glutamate-gated ion channel activity / cellular response to glycine / response to electrical stimulus / ionotropic glutamate receptor complex / asymmetric synapse / Unblocking of NMDA receptors, glutamate binding and activation / G-protein alpha-subunit binding / glutamate receptor binding / positive regulation of synaptic transmission / conditioned place preference / long-term memory / postsynaptic density, intracellular component / regulation of synaptic transmission, glutamatergic / response to fungicide / neuronal action potential / cytoskeletal protein binding / extracellular ligand-gated monoatomic ion channel activity / vesicle-mediated transport / glutamate-gated receptor activity / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / endoplasmic reticulum-Golgi intermediate compartment membrane / somatodendritic compartment / glutamate-gated calcium ion channel activity / synapse assembly / presynaptic active zone membrane / ionotropic glutamate receptor signaling pathway / ionotropic glutamate receptor binding / dendrite cytoplasm / excitatory synapse / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of excitatory postsynaptic potential / cellular response to amino acid stimulus / dendritic shaft / SNARE binding / synaptic membrane / response to cocaine / PDZ domain binding / neuromuscular junction / protein tetramerization / establishment of protein localization / ER to Golgi transport vesicle membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / receptor internalization / cerebral cortex development / regulation of synaptic plasticity / response to nutrient levels / cellular response to growth factor stimulus / recycling endosome / postsynaptic density membrane / modulation of chemical synaptic transmission
Similarity search - Function
Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / 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 ...Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / 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
Protein cornichon homolog 1 / Glutamate receptor 1 / Glutamate receptor 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.76 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_70920.png

Downloads & links

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Map

FileDownload / File: emd_70920.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGluA1A2-CNIH1 rr2b glu (composite map, LBD-TMD)
Projections & slices

Image control

Size
Brightness
Contrast
Others
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 4.7
Minimum - Maximum-30.522268 - 48.769165000000001
Average (Standard dev.)-0.0028124533 (±0.94661105)
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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Sample components

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Entire : Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)

EntireName: Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)
Components
  • Complex: Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)
    • Protein or peptide: Isoform Flip of Glutamate receptor 1
    • Protein or peptide: Isoform Flip of Glutamate receptor 2
    • Protein or peptide: Protein cornichon homolog 1
  • Ligand: GLUTAMIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: N,N'-[biphenyl-4,4'-diyldi(2R)propane-2,1-diyl]dipropane-2-sulfonamide
  • Ligand: SODIUM ION

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Supramolecule #1: Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)

SupramoleculeName: Heteromeric GluA1/A2-CNIH1 + rr2b + glu (LBD-TMD, composite map)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 630 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: 48.285328 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 SKDSGSKDKT SALS LSNVA GVFYILIGGL GLAMLVALIE FCYKSR

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: 47.767008 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 YDKGECGAKD SGSKEKTSAL SLSN VAGVF YILVGGLGLA MLVALIEFCY KSR

UniProtKB: Glutamate receptor 2

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Macromolecule #3: Protein cornichon homolog 1

MacromoleculeName: Protein cornichon homolog 1 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.489604 KDa
SequenceString:
AFTFAAFCYM LALLLTAALI FFAIWHIIAF DELKTDYKNP IDQCNTLNPL VLPEYLIHAF FCVMFLCAAE WLTLGLNMPL LAYHIWRYM SRPVMSGPGL YDPTTIMNAD ILAYCQKEGW CKLAFYLLAF FYYLYGMIYV LVS

UniProtKB: Protein cornichon homolog 1

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Macromolecule #4: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 4 / Number of copies: 4 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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Macromolecule #5: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 5 / Number of copies: 16 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #6: N,N'-[biphenyl-4,4'-diyldi(2R)propane-2,1-diyl]dipropane-2-sulfonamide

MacromoleculeName: N,N'-[biphenyl-4,4'-diyldi(2R)propane-2,1-diyl]dipropane-2-sulfonamide
type: ligand / ID: 6 / Number of copies: 2 / Formula: FWF
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 480.684 Da
Chemical component information

ChemComp-FWF:
N,N'-[biphenyl-4,4'-diyldi(2R)propane-2,1-diyl]dipropane-2-sulfonamide

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Macromolecule #7: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 7 / 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
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 / 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: 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 reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.76 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 76183
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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