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- EMDB-49726: The structure of GluA1/A4 LBD-TMD with 2 TARPs -

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Basic information

Entry
Database: EMDB / ID: EMD-49726
TitleThe structure of GluA1/A4 LBD-TMD with 2 TARPs
Map data
Sample
  • Complex: CP-AMPA receptors
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
    • Protein or peptide: Glutamate receptor 1
    • Protein or peptide: Isoform 2 of Glutamate receptor 4
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
KeywordsiGluR / CP-AMPA receptors / MEMBRANE PROTEIN
Function / homology
Function and homology information


Cargo concentration in the ER / Presynaptic depolarization and calcium channel opening / cellular response to ammonium ion / axonal spine / COPII-mediated vesicle transport / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / response to sucrose / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane ...Cargo concentration in the ER / Presynaptic depolarization and calcium channel opening / cellular response to ammonium ion / axonal spine / COPII-mediated vesicle transport / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / response to sucrose / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / regulation of monoatomic ion transmembrane transport / cellular response to L-glutamate / myosin V binding / LGI-ADAM interactions / neuron spine / positive regulation of AMPA receptor activity / cerebellar mossy fiber / Trafficking of AMPA receptors / proximal dendrite / response to arsenic-containing substance / postsynaptic neurotransmitter receptor diffusion trapping / kainate selective glutamate receptor complex / membrane hyperpolarization / cellular response to dsRNA / regulation of AMPA receptor activity / channel regulator activity / long-term synaptic depression / regulation of synapse structure or activity / ligand-gated calcium channel activity / dendritic spine membrane / beta-2 adrenergic receptor binding / Synaptic adhesion-like molecules / cellular response to peptide hormone stimulus / protein targeting to membrane / nervous system process / spinal cord development / voltage-gated calcium channel complex / cellular response to amine stimulus / response to psychosocial stress / peptide hormone receptor binding / response to morphine / neurotransmitter receptor localization to postsynaptic specialization membrane / Activation of AMPA receptors / behavioral response to pain / perisynaptic space / neuronal cell body membrane / response to lithium ion / Trafficking of GluR2-containing AMPA receptors / negative regulation of smooth muscle cell apoptotic process / AMPA glutamate receptor activity / protein kinase A binding / regulation of receptor recycling / neuronal action potential / neuromuscular junction development / response to electrical stimulus / adenylate cyclase binding / transmission of nerve impulse / AMPA glutamate receptor complex / ionotropic glutamate receptor complex / cellular response to glycine / membrane depolarization / immunoglobulin binding / asymmetric synapse / Unblocking of NMDA receptors, glutamate binding and activation / G-protein alpha-subunit binding / glutamate receptor binding / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of synaptic transmission / conditioned place preference / long-term memory / response to fungicide / postsynaptic density, intracellular component / voltage-gated calcium channel activity / glutamate-gated receptor activity / positive regulation of synaptic transmission, glutamatergic / cellular response to brain-derived neurotrophic factor stimulus / synapse assembly / glutamate-gated calcium ion channel activity / somatodendritic compartment / presynaptic active zone membrane / ionotropic glutamate receptor binding / ionotropic glutamate receptor signaling pathway / excitatory synapse / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / cellular response to amino acid stimulus / hippocampal mossy fiber to CA3 synapse / positive regulation of excitatory postsynaptic potential / response to cocaine / calcium channel regulator activity / dendritic shaft / synaptic membrane / neuromuscular junction / synaptic transmission, glutamatergic / PDZ domain binding / long-term synaptic potentiation / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / receptor internalization / cerebral cortex development / regulation of membrane potential
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
Glutamate receptor 1 / Glutamate receptor 4 / Voltage-dependent calcium channel gamma-2 subunit
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.22 Å
AuthorsFang CL / Gouaux E
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2025
Title: Gating and noelin clustering of native Ca-permeable AMPA receptors.
Authors: Chengli Fang / Cathy J Spangler / Jumi Park / Natalie Sheldon / Laurence O Trussell / Eric Gouaux /
Abstract: AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and have vital roles in synaptic plasticity, motor coordination, learning and memory. Whereas ...AMPA-type ionotropic glutamate receptors (AMPARs) are integral to fast excitatory synaptic transmission and have vital roles in synaptic plasticity, motor coordination, learning and memory. Whereas extensive structural studies have been conducted on recombinant AMPARs and native calcium-impermeable (CI)-AMPARs alongside their auxiliary proteins, the molecular architecture of native calcium-permeable (CP)-AMPARs has remained undefined. Here, to determine the subunit composition, physiological architecture and gating mechanisms of CP-AMPARs, we visualize these receptors, immunoaffinity purified from rat cerebella, and resolve their structures using cryo-electron microscopy (cryo-EM). Our results indicate that the predominant assembly consists of GluA1 and GluA4 subunits, with the GluA4 subunit occupying the B and D positions, and auxiliary subunits, including transmembrane AMPAR regulatory proteins (TARPs) located at the B' and D' positions, and cornichon homologues (CNIHs) or TARPs located at the A' and C' positions. Furthermore, we resolved the structure of the noelin (NOE1)-GluA1-GluA4 complex, in which NOE1 specifically binds to the GluA4 subunit at the B and D positions. Notably, NOE1 stabilizes the amino-terminal domain layer without affecting gating properties of the receptor. NOE1 contributes to AMPAR function by forming dimeric AMPAR assemblies that are likely to engage in extracellular networks, clustering receptors in synaptic environments and modulating receptor responsiveness to synaptic inputs.
History
DepositionMar 14, 2025-
Header (metadata) releaseJul 2, 2025-
Map releaseJul 2, 2025-
UpdateNov 26, 2025-
Current statusNov 26, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_49726.png

Downloads & links

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Map

FileDownload / File: emd_49726.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.88 Å/pix.
x 224 pix.
= 421.12 Å		1.88 Å/pix.
x 224 pix.
= 421.12 Å		1.88 Å/pix.
x 224 pix.
= 421.12 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.664
Minimum - Maximum-2.4107897 - 3.7758145
Average (Standard dev.)0.0010021611 (±0.07162531)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 421.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_49726_additional_1.map
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Half map: #2

Fileemd_49726_half_map_1.map
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Half map: #1

Fileemd_49726_half_map_2.map
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Sample components

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Entire : CP-AMPA receptors

EntireName: CP-AMPA receptors
Components
  • Complex: CP-AMPA receptors
    • Protein or peptide: Voltage-dependent calcium channel gamma-2 subunit
    • Protein or peptide: Glutamate receptor 1
    • Protein or peptide: Isoform 2 of Glutamate receptor 4
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid

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Supramolecule #1: CP-AMPA receptors

SupramoleculeName: CP-AMPA receptors / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Voltage-dependent calcium channel gamma-2 subunit

MacromoleculeName: Voltage-dependent calcium channel gamma-2 subunit / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 22.589975 KDa
SequenceString: DRGVQMLLTT VGAFAAFSLM TIAVGTDYWL YSRGVCKTKS VSENETSKKN EEVMTHSGLW RTCCLEGNFK GLCKQIDHFP EDADYEADT AEYFLRAVRA SSIFPILSVI LLFMGGLCIA ASEFYKTRHN IILSAGIFFV SAGLSNIIGI IVYISANAGD P SKSDSKKN ...String:
DRGVQMLLTT VGAFAAFSLM TIAVGTDYWL YSRGVCKTKS VSENETSKKN EEVMTHSGLW RTCCLEGNFK GLCKQIDHFP EDADYEADT AEYFLRAVRA SSIFPILSVI LLFMGGLCIA ASEFYKTRHN IILSAGIFFV SAGLSNIIGI IVYISANAGD P SKSDSKKN SYSYGWSFYF GALSFIIAEM VGVLAVHMFI DRHKQL

UniProtKB: Voltage-dependent calcium channel gamma-2 subunit

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Macromolecule #2: Glutamate receptor 1

MacromoleculeName: Glutamate receptor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 47.879855 KDa
SequenceString: RTYIVTTILE DPYVMLKKNA NQFEGNDRYE GYCVELAAEI AKHVGYSYRL EIVSDGKYGA RDPDTKAWNG MVGELVYGRA DVAVAPLTI TLVREEVIDF SKPFMSLGIS IMIKKPQKSK PGVFSFLDPL AYEIWMCIVF AYIGVSVVLF LVSRFSPYEW H SEEFEEGR ...String:
RTYIVTTILE DPYVMLKKNA NQFEGNDRYE GYCVELAAEI AKHVGYSYRL EIVSDGKYGA RDPDTKAWNG MVGELVYGRA DVAVAPLTI TLVREEVIDF SKPFMSLGIS IMIKKPQKSK PGVFSFLDPL AYEIWMCIVF AYIGVSVVLF LVSRFSPYEW H SEEFEEGR DQTTSDQSNE FGIFNSLWFS LGAFMQQGCD ISPRSLSGRI VGGVWWFFTL IIISSYTANL AAFLTVERMV SP IESAEDL AKQTEIAYGT LEAGSTKEFF RRSKIAVFEK MWTYMKSAEP SVFVRTTEEG MIRVRKSKGK YAYLLESTMN EYI EQRKPC DTMKVGGNLD SKGYGIATPK GSALRNPVNL AVLKLNEQGL LDKLKNKWWY DKGECGSGGG DSKDKTSALS LSNV AGVFY ILIGGLGLAM LVALIEFCYK SR

UniProtKB: Glutamate receptor 1

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Macromolecule #3: Isoform 2 of Glutamate receptor 4

MacromoleculeName: Isoform 2 of Glutamate receptor 4 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 47.173348 KDa
SequenceString: VVVTTIMESP YVMYKKNHEM FEGNDKYEGY CVDLASEIAK HIGIKYKIAI VPDGKYGARD ADTKIWNGMV GELVYGKAEI AIAPLTITL VREEVIDFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVVLFLV SRFSPYEWHT E EPEDGKEG ...String:
VVVTTIMESP YVMYKKNHEM FEGNDKYEGY CVDLASEIAK HIGIKYKIAI VPDGKYGARD ADTKIWNGMV GELVYGKAEI AIAPLTITL VREEVIDFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVVLFLV SRFSPYEWHT E EPEDGKEG PSDQPPNEFG IFNSLWFSLG AFMQQGCDIS PRSLSGRIVG GVWWFFTLII ISSYTANLAA FLTVERMVSP IE SAEDLAK QTEIAYGTLD SGSTKEFFRR SKIAVYEKMW TYMRSAEPSV FTRTTAEGVA RVRKSKGKFA FLLESTMNEY TEQ RKPCDT MKVGGNLDSK GYGVATPKGS SLRTPVNLAV LKLSEAGVLD KLKNKWWYDK GECGPKDSGS KDKTSALSLS NVAG VFYIL VGGLGLAMLV ALIEFCYKS

UniProtKB: Glutamate receptor 4

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Macromolecule #4: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquino...

MacromoleculeName: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
type: ligand / ID: 4 / Number of copies: 4 / Formula: ZK1
Molecular weightTheoretical: 409.254 Da
Chemical component information

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / medication*YM

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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

Concentration0.1 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: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 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: NONE
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 27128
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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