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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


Presynaptic depolarization and calcium channel opening / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose ...Presynaptic depolarization and calcium channel opening / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose / cerebellar mossy fiber / postsynaptic neurotransmitter receptor diffusion trapping / neuron spine / myosin V binding / kainate selective glutamate receptor complex / Trafficking of AMPA receptors / channel regulator activity / regulation of AMPA receptor activity / LGI-ADAM interactions / proximal dendrite / regulation of monoatomic ion transmembrane transport / response to arsenic-containing substance / cellular response to dsRNA / cellular response to L-glutamate / membrane hyperpolarization / regulation of synapse structure or activity / dendritic spine membrane / nervous system process / long-term synaptic depression / Synaptic adhesion-like molecules / beta-2 adrenergic receptor binding / protein targeting to membrane / voltage-gated calcium channel complex / cellular response to peptide hormone stimulus / response to morphine / neuronal cell body membrane / protein kinase A binding / neurotransmitter receptor localization to postsynaptic specialization membrane / peptide hormone receptor binding / cellular response to amine stimulus / response to psychosocial stress / neuromuscular junction development / spinal cord development / Activation of AMPA receptors / perisynaptic space / AMPA glutamate receptor activity / transmission of nerve impulse / negative regulation of smooth muscle cell apoptotic process / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / behavioral response to pain / AMPA glutamate receptor complex / adenylate cyclase binding / ionotropic glutamate receptor complex / immunoglobulin binding / asymmetric synapse / conditioned place preference / excitatory synapse / membrane depolarization / response to electrical stimulus / regulation of receptor recycling / G-protein alpha-subunit binding / positive regulation of excitatory postsynaptic potential / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / positive regulation of synaptic transmission / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / regulation of postsynaptic membrane neurotransmitter receptor levels / neuronal action potential / voltage-gated calcium channel activity / response to fungicide / glutamate-gated receptor activity / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / somatodendritic compartment / ionotropic glutamate receptor binding / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / synaptic membrane / hippocampal mossy fiber to CA3 synapse / dendritic shaft / regulation of membrane potential / calcium channel regulator activity / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / response to cocaine / synaptic transmission, glutamatergic / PDZ domain binding / cellular response to amino acid stimulus / neuromuscular junction / response to nutrient levels / response to calcium ion / response to peptide hormone / postsynaptic density membrane / modulation of chemical synaptic transmission / recycling endosome / regulation of synaptic plasticity
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 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 CF / 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-
UpdateJul 9, 2025-
Current statusJul 9, 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
Brightness
Contrast
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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 / antagonist, 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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