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- EMDB-46875: Desensitized state 1 of the GluA2-gamma2 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-46875
TitleDesensitized state 1 of the GluA2-gamma2 complex
Map dataDesensitized state 1 LBD-TMD locally sharpened map
Sample
  • Complex: GluA2-TARPgamma2 Complex
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: GLUTAMIC ACID
Keywordsligand-gated ion channel / ionotropic glutamate receptor / ampa receptor / ion channel / TRANSPORT 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 / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / regulation of AMPA receptor activity / membrane hyperpolarization / nervous system process ...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 / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / regulation of AMPA receptor activity / membrane hyperpolarization / nervous system process / protein targeting to membrane / voltage-gated calcium channel complex / spine synapse / dendritic spine neck / dendritic spine head / cellular response to amine stimulus / neurotransmitter receptor localization to postsynaptic specialization membrane / neuromuscular junction development / perisynaptic space / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / transmission of nerve impulse / response to lithium ion / Trafficking of GluR2-containing AMPA receptors / kainate selective glutamate receptor activity / AMPA glutamate receptor complex / cellular response to glycine / extracellularly glutamate-gated ion channel activity / immunoglobulin binding / asymmetric synapse / ionotropic glutamate receptor complex / conditioned place preference / regulation of receptor recycling / membrane depolarization / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of synaptic transmission / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of synaptic transmission, glutamatergic / voltage-gated calcium channel activity / response to fungicide / cytoskeletal protein binding / glutamate-gated receptor activity / regulation of long-term synaptic depression / extracellular ligand-gated monoatomic ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / presynaptic active zone membrane / glutamate-gated calcium ion channel activity / somatodendritic compartment / dendrite membrane / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / synaptic membrane / hippocampal mossy fiber to CA3 synapse / dendritic shaft / SNARE binding / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / establishment of protein localization / response to calcium ion / postsynaptic density membrane / cerebral cortex development / modulation of chemical synaptic transmission / receptor internalization / Schaffer collateral - CA1 synapse / terminal bouton / synaptic vesicle / synaptic vesicle membrane / presynapse / signaling receptor activity / amyloid-beta binding / presynaptic membrane / growth cone / scaffold protein binding / perikaryon / chemical synaptic transmission / dendritic spine / postsynaptic membrane / neuron projection / postsynaptic density / axon / external side of plasma membrane / neuronal cell body / dendrite / synapse / protein kinase binding / protein-containing complex binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / plasma membrane
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 / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel ...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 / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / 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: 4.48 Å
AuthorsKumar Mondal A / Carrillo E / Jayaraman V / Twomey EC
Funding support United States, 4 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM154904 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM122528 United States
Other privateKinship Foundation 22098168
Other privateDiana Helis Henry Medical Research Foundation 142548
CitationJournal: Nature / Year: 2025
Title: Glutamate gating of AMPA-subtype iGluRs at physiological temperatures.
Authors: Anish Kumar Mondal / Elisa Carrillo / Vasanthi Jayaraman / Edward C Twomey /
Abstract: Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission. iGluRs are gated by glutamate, where on glutamate binding, they open ...Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion channel helices hinging away from the pore axis in a motif that is conserved across all iGluRs. Desensitization occurs when the local dimer pairs decouple and enables closure of the ion channel below through restoring the channel hinges and refolding the channel gate. Our findings define how glutamate gates iGluRs, provide foundations for therapeutic design and demonstrate how physiological temperatures can alter iGluR function.
History
DepositionSep 4, 2024-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateJun 4, 2025-
Current statusJun 4, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46875.png

Downloads & links

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Map

FileDownload / File: emd_46875.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDesensitized state 1 LBD-TMD locally sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.97 Å/pix.
x 440 pix.
= 426.8 Å		0.97 Å/pix.
x 440 pix.
= 426.8 Å		0.97 Å/pix.
x 440 pix.
= 426.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.97 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.552285 - 0.79860634
Average (Standard dev.)0.00076926185 (±0.011373058)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 426.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Desensitized state 1 TMD half map

Fileemd_46875_additional_1.map
AnnotationDesensitized state 1 TMD half map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Additional map: Desensitized state 1 TMD locally sharpened map

Fileemd_46875_additional_2.map
AnnotationDesensitized state 1 TMD locally sharpened map
Projections & Slices
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Histogram

Histogram (log scale)

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Additional map: Desensitized state 1 TMD half map

Fileemd_46875_additional_3.map
AnnotationDesensitized state 1 TMD half map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: Desensitized state 1 LBD-TMD half map

Fileemd_46875_half_map_1.map
AnnotationDesensitized state 1 LBD-TMD half map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Desensitized state 1 LBD-TMD half map

Fileemd_46875_half_map_2.map
AnnotationDesensitized state 1 LBD-TMD half map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : GluA2-TARPgamma2 Complex

EntireName: GluA2-TARPgamma2 Complex
Components
  • Complex: GluA2-TARPgamma2 Complex
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Protein or peptide: Isoform Flip of Glutamate receptor 2
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: GluA2-TARPgamma2 Complex

SupramoleculeName: GluA2-TARPgamma2 Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Isoform Flip of Glutamate receptor 2

MacromoleculeName: Isoform Flip of Glutamate receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 47.938141 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EQKTVVVTTI LESPYVMMKK NHEMLEGNER YEGYCVDLAA EIAKHCGFKY KLTIVGDGKY GARDADTKIW NGMVGELVYG KADIAIAPL TITLVREEVI DFSKPFMSLG ISIMIKKPQK SKPGVFSFLD PLAYEIWMCI VFAYIGVSVV LFLVSRFSPY E WHTEEFED ...String:
EQKTVVVTTI LESPYVMMKK NHEMLEGNER YEGYCVDLAA EIAKHCGFKY KLTIVGDGKY GARDADTKIW NGMVGELVYG KADIAIAPL TITLVREEVI DFSKPFMSLG ISIMIKKPQK SKPGVFSFLD PLAYEIWMCI VFAYIGVSVV LFLVSRFSPY E WHTEEFED GRETQSSEST NEFGIFNSLW FSLGAFMQQG CDISPRSLSG RIVGGVWWFF TLIIISSYTA NLAAFLTVER MV SPIESAE DLSKQTEIAY GTLDSGSTKE FFRRSKIAVF DKMWTYMRSA EPSVFVRTTA EGVARVRKSK GKYAYLLEST MNE YIEQRK PCDTMKVGGN LDSKGYGIAT PKGSSLGTPV NLAVLKLSEQ GVLDKLKNKW WYDKGECGAK DSGSKEKTSA LSLS NVAGV FYILVGGLGL AMLVALIEFC YKSRA

UniProtKB: Glutamate receptor 2

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Macromolecule #2: Voltage-dependent calcium channel gamma-2 subunit

MacromoleculeName: Voltage-dependent calcium channel gamma-2 subunit / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 22.633041 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RGVQMLLTTV GAFAAFSLMT IAVGTDYWLY SRGVCKTKSV SENETSKKNE EVMTHSGLWR TCCLEGNFKG LCKQIDHFPE DADYEADTA EYFLRAVRAS SIFPILSVIL LFMGGLCIAA SEFYKTRHNI ILSAGIFFVS AGLSNIIGII VYISANAGDP S KSDSKKNS ...String:
RGVQMLLTTV GAFAAFSLMT IAVGTDYWLY SRGVCKTKSV SENETSKKNE EVMTHSGLWR TCCLEGNFKG LCKQIDHFPE DADYEADTA EYFLRAVRAS SIFPILSVIL LFMGGLCIAA SEFYKTRHNI ILSAGIFFVS AGLSNIIGII VYISANAGDP S KSDSKKNS YSYGWSFYFG ALSFIIAEMV GVLAVHMFID RHKQLTG

UniProtKB: Voltage-dependent calcium channel gamma-2 subunit

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Macromolecule #3: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 3 / 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

Concentration4 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab initio
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.48 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 44872
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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