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- EMDB-54065: GluA4 in complex with TARP-2, Resting II state, structure of TMD/... -

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Basic information

Entry
Database: EMDB / ID: EMD-54065
TitleGluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domains
Map data
Sample
  • Complex: GluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domain
    • Protein or peptide: Isoform 2 of Glutamate receptor 4
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Ligand: 6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide
KeywordsGria4 / Voltage-dependent calcium channel gamma-2 / AMPA Receptor / GluA4-TARP2 / Membrane protein / Resting state II / TMD/LBD
Function / homology
Function and homology information


Presynaptic depolarization and calcium channel opening / 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 / channel regulator activity / Trafficking of AMPA receptors / kainate selective glutamate receptor complex / LGI-ADAM interactions ...Presynaptic depolarization and calcium channel opening / 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 / channel regulator activity / Trafficking of AMPA receptors / kainate selective glutamate receptor complex / LGI-ADAM interactions / regulation of synapse structure or activity / membrane hyperpolarization / nervous system process / Synaptic adhesion-like molecules / protein targeting to membrane / voltage-gated calcium channel complex / neurotransmitter receptor localization to postsynaptic specialization membrane / neuromuscular junction development / Activation of AMPA receptors / AMPA glutamate receptor activity / transmission of nerve impulse / negative regulation of smooth muscle cell apoptotic process / Trafficking of GluR2-containing AMPA receptors / AMPA glutamate receptor complex / ionotropic glutamate receptor complex / membrane depolarization / Unblocking of NMDA receptors, glutamate binding and activation / positive regulation of synaptic transmission, glutamatergic / regulation of postsynaptic membrane neurotransmitter receptor levels / voltage-gated calcium channel activity / response to fungicide / glutamate-gated receptor activity / presynaptic active zone membrane / somatodendritic compartment / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / hippocampal mossy fiber to CA3 synapse / regulation of membrane potential / calcium channel regulator activity / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / postsynaptic density membrane / response to calcium ion / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / terminal bouton / chemical synaptic transmission / dendritic spine / postsynaptic density / neuronal cell body / synapse / dendrite / glutamatergic synapse / cell surface / identical protein binding / 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
Glutamate receptor 4 / Voltage-dependent calcium channel gamma-2 subunit
Similarity search - Component
Biological speciesRattus novergicus (Norway rat) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsVega-Gutierrez C / Herguedas B
Funding support Spain, 1 items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PID2019-106284GA-I00 Spain
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: GluA4 AMPA receptor gating mechanisms and modulation by auxiliary proteins.
Authors: Carlos Vega-Gutiérrez / Javier Picañol-Párraga / Irene Sánchez-Valls / Victoria Del Pilar Ribón-Fuster / David Soto / Beatriz Herguedas /
Abstract: AMPA-type glutamate receptors, fundamental ion channels for fast excitatory neurotransmission and synaptic plasticity, contain a GluA tetrameric core surrounded by auxiliary proteins such as ...AMPA-type glutamate receptors, fundamental ion channels for fast excitatory neurotransmission and synaptic plasticity, contain a GluA tetrameric core surrounded by auxiliary proteins such as transmembrane AMPA receptor regulatory proteins (TARPs) or Cornichons. Their exact composition and stoichiometry govern functional properties, including kinetics, calcium permeability and trafficking. The GluA1-GluA3 subunits predominate in the adult forebrain and are well characterized. However, we lack structural information on full-length GluA4-containing AMPARs, a subtype that has specific roles in brain development and specific cell types in mammals. Here we present the cryo-electron microscopy structures of rat GluA4:TARP-γ2 trapped in active, resting and desensitized states, covering a full gating cycle. Additionally, we describe the structure of GluA4 alone, which displays a classical Y-shaped conformation. In resting conditions, GluA4:TARP-γ2 adopts two conformations, one resembling the desensitized states of other GluA subunits. Moreover, we identify a regulatory site for TARP-γ2 in the ligand-binding domain that modulates gating kinetics. Our findings uncover distinct features of GluA4, highlighting how subunit composition and auxiliary proteins shape receptor structure and dynamics, expanding glutamatergic signaling diversity.
History
DepositionJun 18, 2025-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54065.png

Downloads & links

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Map

FileDownload / File: emd_54065.map.gz / Format: CCP4 / Size: 465.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 496 pix.
= 320.515 Å		0.65 Å/pix.
x 496 pix.
= 320.515 Å		0.65 Å/pix.
x 496 pix.
= 320.515 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6462 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.19
Minimum - Maximum-0.3177171 - 0.63695455
Average (Standard dev.)0.0013741368 (±0.02752229)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions496496496
Spacing496496496
CellA=B=C: 320.5152 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54065_msk_1.map
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Half map: #2

Fileemd_54065_half_map_1.map
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Half map: #1

Fileemd_54065_half_map_2.map
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Sample components

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Entire : GluA4 in complex with TARP-2, Resting II state, structure of TMD/...

EntireName: GluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domain
Components
  • Complex: GluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domain
    • Protein or peptide: Isoform 2 of Glutamate receptor 4
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
  • Ligand: 6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide

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Supramolecule #1: GluA4 in complex with TARP-2, Resting II state, structure of TMD/...

SupramoleculeName: GluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus novergicus (Norway rat)
Molecular weightTheoretical: 620 KDa

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Macromolecule #1: Isoform 2 of Glutamate receptor 4

MacromoleculeName: Isoform 2 of Glutamate receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 98.671938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GAFPSSVQIG GLFIRNTDQE YTAFRLAIFL HNTSPNASEA PFNLVPHVDN IETANSFAVT NAFCSQYSRG VFAIFGLYDK RSVHTLTSF CSALHISLIT PSFPTEGESQ FVLQLRPSLR GALLSLLDHY EWNCFVFLYD TDRGYSILQA IMEKAGQNGW H VSAICVEN ...String:
GAFPSSVQIG GLFIRNTDQE YTAFRLAIFL HNTSPNASEA PFNLVPHVDN IETANSFAVT NAFCSQYSRG VFAIFGLYDK RSVHTLTSF CSALHISLIT PSFPTEGESQ FVLQLRPSLR GALLSLLDHY EWNCFVFLYD TDRGYSILQA IMEKAGQNGW H VSAICVEN FNDVSYRQLL EELDRRQEKK FVIDCEIERL QNILEQIVSV GKHVKGYHYI IANLGFKDIS LERFIHGGAN VT GFQLVDF NTPMVTKLMD RWKKLDQREY PGSETPPKYT SALTYDGVLV MAETFRSLRR QKIDISRRGN AGDCLANPAA PWG QGIDME RTLKQVRIQG LTGNVQFDHY GRRVNYTMDV FELKSTGPRK VGYWNDMDKL VLIQDMPTLG NDTAAIENRT VVVT TIMES PYVMYKKNHE MFEGNDKYEG YCVDLASEIA KHIGIKYKIA IVPDGKYGAR DADTKIWNGM VGELVYGKAE IAIAP LTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFSPYEWH TEEPED GKE GPSDQPPNEF GIFNSLWFSL GAFMQQGCDI SPRSLSGRIV GGVWWFFTLI IISSYTANLA AFLTVERMVS PIESAED LA KQTEIAYGTL DSGSTKEFFR RSKIAVYEKM WTYMRSAEPS VFTRTTAEGV ARVRKSKGKF AFLLESTMNE YIEQRKPC D TMKVGGNLDS KGYGVATPKG SSLRTPVNLA VLKLSEAGVL DKLKNKWWYD KGECGPKDSG SKDKTSALSL SNVAGVFYI LVGGLGLAML VALIEFCYKS RAEAKRMKLT FSEATRNKAR LSITGSVGEN GRVLTPDCPK AVHTGTAIRQ SSGLAVIASD LP

UniProtKB: Glutamate receptor 4

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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: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 35.950801 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGLFDRGVQM LLTIVGAFAA FSLMTIAVGT DYWLYSRGVC KTKSVSENET SKKNEEVMTH SGLWRTCCLE GNFKGLCKQI DHFPEDADY EADTAEYFLR AVRASSIFPI LSVILLFMGG LCIAASEFYK TRHNIILSAG IFFVSAGLSN IIGIIVYISA N AGDPSKSD ...String:
MGLFDRGVQM LLTIVGAFAA FSLMTIAVGT DYWLYSRGVC KTKSVSENET SKKNEEVMTH SGLWRTCCLE GNFKGLCKQI DHFPEDADY EADTAEYFLR AVRASSIFPI LSVILLFMGG LCIAASEFYK TRHNIILSAG IFFVSAGLSN IIGIIVYISA N AGDPSKSD SKKNSYSYGW SFYFGALSFI IAEMVGVLAV HMFIDRHKQL RATARATDYL QASAITRIPS YRYRYQRRSR SS SRSTEPS HSRDASPVGV KGFNTLPSTE ISMYTLSRDP LKAATTPTAT YNSDRDNSFL QVHNCIQKDS KDSLHANTAN RRT TPV

UniProtKB: Voltage-dependent calcium channel gamma-2 subunit

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Macromolecule #3: 6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-s...

MacromoleculeName: 6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide
type: ligand / ID: 3 / Number of copies: 4 / Formula: E2Q
Molecular weightTheoretical: 336.28 Da
Chemical component information

ChemComp-E2Q:
6-nitro-2,3-bis(oxidanylidene)-1,4-dihydrobenzo[f]quinoxaline-7-sulfonamide

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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

Concentration3.55 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMNH2C(CH2OH)3Tris(hydroxymethyl)aminomethane
0.02 %C56H92O25Glyco-diosgenin (GDN)
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
DetailsThe sample was incubated with the AMPA receptor antagonist (NBQX) to capture the receptor in its resting state

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Number real images: 56948 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
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: An Ab-initio Reconstruction was generated in CryoSPARC 4.3.1
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.3.1) / Number images used: 35082
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationDetails: 3D classification without alignment
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

4o3b

chain_id: C, source_name: PDB, initial_model_type: experimental model

4u2r

chain_id: B, source_name: PDB, initial_model_type: experimental model

9qdn

chain_id: A, source_name: PDB, initial_model_type: experimental model

9qdn

chain_id: D, source_name: PDB, initial_model_type: experimental model
DetailsI performed fitting using Chimera for the TMD domain (previously modeled and individually deposited in the PDB), along with the following LBDs: LBD monomers from GluA4G2 Resting I (PDB ID: 9QDN) were fitted into chains A and D, while PDB entry 4U2R (GluA2 LBD, apo state) and PDB entry 4O3B (GluA2, aspartate-bound) were fitted into chains B and C, respectively. B-factors were reset, GluA4 residues were substituted, water molecules were removed, and NBQX was introduced. Subsequently, rigid-body refinement was performed using Phenix.
RefinementProtocol: RIGID BODY FIT
Output model

PDB-9rms:
GluA4 in complex with TARP-2, Resting II state, structure of TMD/LBD domains

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