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- EMDB-76093: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degr... -

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Basic information

Entry
Database: EMDB / ID: EMD-76093
TitleGluA2-STZ open state with full agonist glutamate (Glu) at 25 degrees C (full-length composite)
Map dataETS Glu open composite
Sample
  • Complex: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degrees C (full-length composite)
    • Protein or peptide: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit chimera
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: SODIUM ION
  • Ligand: GLUTAMIC ACID
Keywordsionotropic glutamate receptor (iGluR) / iGluR / GluA2 / transmembrane AMPAR regulatory protein (TARP) y2 / gamma2 / stargazin (STZ) / MEMBRANE PROTEIN
Function / homology
Function and homology information


Presynaptic depolarization and calcium channel opening / LGI-ADAM interactions / Trafficking of AMPA receptors / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / positive regulation of AMPA receptor activity / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / membrane hyperpolarization / regulation of AMPA receptor activity ...Presynaptic depolarization and calcium channel opening / LGI-ADAM interactions / Trafficking of AMPA receptors / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / positive regulation of AMPA receptor activity / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / membrane hyperpolarization / regulation of AMPA receptor activity / channel regulator activity / protein targeting to membrane / nervous system process / voltage-gated calcium channel complex / regulation of synaptic plasticity by chemical substance / spine synapse / dendritic spine neck / dendritic spine cytoplasm / dendritic spine head / cellular response to amine stimulus / neurotransmitter receptor localization to postsynaptic specialization membrane / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / perisynaptic space / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / AMPA glutamate receptor activity / AMPA glutamate receptor clustering / regulation of receptor recycling / neuromuscular junction development / kainate selective glutamate receptor activity / transmission of nerve impulse / AMPA glutamate receptor complex / extracellularly glutamate-gated ion channel activity / ionotropic glutamate receptor complex / membrane depolarization / cellular response to glycine / immunoglobulin binding / asymmetric synapse / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of synaptic transmission / conditioned place preference / regulation of synaptic transmission, glutamatergic / response to fungicide / voltage-gated calcium channel activity / cytoskeletal protein binding / extracellular ligand-gated monoatomic ion channel activity / glutamate-gated receptor activity / cellular response to brain-derived neurotrophic factor stimulus / positive regulation of synaptic transmission, glutamatergic / regulation of long-term synaptic depression / glutamate-gated calcium ion channel activity / somatodendritic compartment / presynaptic active zone membrane / ionotropic glutamate receptor binding / ionotropic glutamate receptor signaling pathway / excitatory synapse / dendrite cytoplasm / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / hippocampal mossy fiber to CA3 synapse / positive regulation of excitatory postsynaptic potential / dendritic shaft / SNARE binding / synaptic membrane / establishment of protein localization / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / long-term synaptic potentiation / receptor internalization / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cerebral cortex development / regulation of membrane potential / response to calcium ion / postsynaptic density membrane / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / terminal bouton / synaptic vesicle membrane / presynapse / synaptic vesicle / amyloid-beta binding / signaling receptor activity / growth cone / scaffold protein binding / chemical synaptic transmission / presynaptic membrane / dendritic spine / perikaryon / postsynaptic membrane / neuron projection / postsynaptic density / external side of plasma membrane / axon / neuronal cell body / dendrite / protein kinase binding
Similarity search - Function
Voltage-dependent calcium channel, gamma-2 subunit / : / PMP-22/EMP/MP20/Claudin family / 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 / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site ...Voltage-dependent calcium channel, gamma-2 subunit / : / PMP-22/EMP/MP20/Claudin family / 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 / 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
Voltage-dependent calcium channel gamma-2 subunit / Glutamate receptor 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.58 Å
AuthorsNewton TP / Yen LY / Gangwar SP / Sobolevsky AI
Funding support United States, 7 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS147755 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)F31NS132554 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 Struct Mol Biol / Year: 2026
Title: Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists.
Authors: Thomas P Newton / Muhammed Aktolun / Maria V Yelshanskaya / Alexey A Alekseev / Laura Y Yen / Shanti Pal Gangwar / Ivan A Sobolevsky / Maria G Kurnikova / Alexander I Sobolevsky /
Abstract: AMPA receptors (AMPARs) mediate fast excitatory neurotransmission. Gating of AMPARs starts with agonist binding and transition into a non-conducting pre-active state, followed by transition into ...AMPA receptors (AMPARs) mediate fast excitatory neurotransmission. Gating of AMPARs starts with agonist binding and transition into a non-conducting pre-active state, followed by transition into conducting open or non-conducting desensitized states. While the terminal apo, open and desensitized states have been structurally characterized, the intermediate pre-active state has remained an enigma. Compared to full agonist glutamate, partial agonists reduce the maximal occupancy of the open state and increase the probability of the pre-active state occurrence. Here we use different partial agonists and time-resolved cryo-electron microscopy (cryo-EM) to capture a structural ensemble of GluA2-γ2 AMPAR complexes in the closed apo, pre-active, open and desensitized states. Binding of partial agonists to the ligand-binding domain (LBD) results in different extents of LBD clamshell closure, with closures exceeding a threshold of ~17° resulting in the open and desensitized states and smaller closures stabilizing the pre-active state. The pre-active state has a distinct gate conformation intermediate between the other two discrete states, completely open and closed. Combined with single-channel current recordings and molecular dynamics simulations, our structural results reveal the complete gating pathway of AMPARs and shed light on the molecular mechanisms of partial agonism and pre-activation.
History
DepositionMar 15, 2026-
Header (metadata) releaseSep 23, 2026-
Map releaseSep 23, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76093.png

Downloads & links

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Map

FileDownload / File: emd_76093.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationETS Glu open composite
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.09 Å/pix.
x 320 pix.
= 348. Å		1.09 Å/pix.
x 320 pix.
= 348. Å		1.09 Å/pix.
x 320 pix.
= 348. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0875 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-27.123795000000001 - 40.826774999999998
Average (Standard dev.)-0.0073868474 (±1.0297538)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 348.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : GluA2-STZ open state with full agonist glutamate (Glu) at 25 degr...

EntireName: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degrees C (full-length composite)
Components
  • Complex: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degrees C (full-length composite)
    • Protein or peptide: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit chimera
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: SODIUM ION
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degr...

SupramoleculeName: GluA2-STZ open state with full agonist glutamate (Glu) at 25 degrees C (full-length composite)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 470 KDa

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Macromolecule #1: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium ch...

MacromoleculeName: Isoform Flip of Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit chimera
type: protein_or_peptide / ID: 1
Details: rat GluA2 covalently fused with mouse STZ,rat GluA2 covalently fused with mouse STZ
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 117.433383 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGKIMHISVL LSPVLWGLIF GVSSNSIQIG GLFPRGADQE YSAFRVGMVQ FSTSEFRLTP HIDNLEVANS FAVTNAFCSQ FSRGVYAIF GFYDKKSVNT ITSFCGTLHV SFITPSFPTD GTHPFVIQMR PDLKGALLSL IEYYQWDKFA YLYDSDRGLS T LQAVLDSA ...String:
MGKIMHISVL LSPVLWGLIF GVSSNSIQIG GLFPRGADQE YSAFRVGMVQ FSTSEFRLTP HIDNLEVANS FAVTNAFCSQ FSRGVYAIF GFYDKKSVNT ITSFCGTLHV SFITPSFPTD GTHPFVIQMR PDLKGALLSL IEYYQWDKFA YLYDSDRGLS T LQAVLDSA AEKKWQVTAI NVGNINNDKK DETYRSLFQD LELKKERRVI LDCERDKVND IVDQVITIGK HVKGYHYIIA NL GFTDGDL LKIQFGGAEV SGFQIVDYDD SLVSKFIERW STLEEKEYPG AHTATIKYTS ALTYDAVQVM TEAFRNLRKQ RIE ISRRGN AGDCLANPAV PWGQGVEIER ALKQVQVEGL SGNIKFDQNG KRINYTINIM ELKTNGPRKI GYWSEVDKMV LTED DTSGL EQKTVVVTTI LESPYVMMKK NHEMLEGNER YEGYCVDLAA EIAKHCGFKY KLTIVGDGKY GARDADTKIW NGMVG ELVY GKADIAIAPL TITLVREEVI DFSKPFMSLG ISIMIKKPQK SKPGVFSFLD PLAYEIWMCI VFAYIGVSVV LFLVSR FSP YEWHTEEFED GRETQSSEST NEFGIFNSLW FSLGAFMQQG CDISPRSLSG RIVGGVWWFF TLIIISSYTA NLAAFLT VE RMVSPIESAE DLSKQTEIAY GTLDSGSTKE FFRRSKIAVF DKMWTYMRSA EPSVFVRTTA EGVARVRKSK GKYAYLLE S TMNEYIEQRK PCDTMKVGGN LDSKGYGIAT PKGSSLGTPV NLAVLKLSEQ GVLDKLKNKW WYDKGECGAK DSGSKEKTS ALSLSNVAGV FYILVGGLGL AMLVALIEFC YKSRAEAKRM KGTGLFDRGV QMLLTTVGAF AAFSLMTIAV GTDYWLYSRG VCKTKSVSE DETSKKNEEV MTHSGLWRTC CLEGNFKGLC KQIDHFPEDA DYEADTAEYF LRAVRASSIF PILSVILLFM G GLCIAASE FYKTRHNIIL SAGIFFVSAG LSNIIGIIVY ISANAGDPSK SDSKKNSYSY GWSFYFGALS FIIAEMVGVL AV HMFIDRH KQLT

UniProtKB: Glutamate receptor 2, Voltage-dependent calcium channel gamma-2 subunit

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Macromolecule #2: (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: 2 / Number of copies: 20 / 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 #3: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 3 / Number of copies: 2
Molecular weightTheoretical: 22.99 Da

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMC4H11NO3Tris-HCl
0.05 %C56H92O29digitonin
1.0 mMC5H9NO4glutamate (Glu)

Details: 150 mM NaCl, 20 mM Tris-HCl pH 8.0, and 0.05% digitonin, 1 mM Glu
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: HOMEMADE PLUNGER
DetailsMonodisperse, multiview particles

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 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: 3677201
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: initial model from experimental data
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 / Number images used: 35236
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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