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- PDB-9p9f: Active substate 4 of the GluA4 homotetramer. -

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Basic information

Entry
Database: PDB / ID: 9p9f
TitleActive substate 4 of the GluA4 homotetramer.
Components
  • Isoform 2 of Glutamate receptor 4
  • Voltage-dependent calcium channel gamma-2 subunit
KeywordsMEMBRANE PROTEIN / AMPAR / Ion Channel / Glutamate Receptor / Ligand-gated
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 / Trafficking of AMPA receptors / postsynaptic neurotransmitter receptor diffusion trapping / kainate selective glutamate receptor complex ...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 / Trafficking of AMPA receptors / postsynaptic neurotransmitter receptor diffusion trapping / kainate selective glutamate receptor complex / membrane hyperpolarization / regulation of AMPA receptor activity / channel regulator activity / regulation of synapse structure or activity / Synaptic adhesion-like molecules / protein targeting to membrane / nervous system process / voltage-gated calcium channel complex / neurotransmitter receptor localization to postsynaptic specialization membrane / Activation of AMPA receptors / Trafficking of GluR2-containing AMPA receptors / negative regulation of smooth muscle cell apoptotic process / AMPA glutamate receptor activity / neuromuscular junction development / transmission of nerve impulse / AMPA glutamate receptor complex / ionotropic glutamate receptor complex / membrane depolarization / Unblocking of NMDA receptors, glutamate binding and activation / regulation of postsynaptic membrane neurotransmitter receptor levels / response to fungicide / voltage-gated calcium channel activity / glutamate-gated receptor activity / positive regulation of synaptic transmission, glutamatergic / somatodendritic compartment / presynaptic active zone membrane / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / hippocampal mossy fiber to CA3 synapse / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of membrane potential / response to calcium ion / postsynaptic density membrane / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / terminal bouton / chemical synaptic transmission / dendritic spine / postsynaptic membrane / postsynaptic density / neuronal cell body / dendrite / synapse / 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 / 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
CYCLOTHIAZIDE / GLUTAMIC ACID / Voltage-dependent calcium channel gamma-2 subunit / Glutamate receptor 4
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.89 Å
AuthorsHale, W.D. / Huganir, R.L. / Twomey, E.C.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)K99MH132811 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R37NS036715 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM154904 United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for activation and conformational plasticity of the GluA4 AMPA receptor.
Authors: W D Hale / Haobo Wang / Richard L Huganir / Edward C Twomey /
Abstract: AMPA-subtype glutamate receptors (AMPARs) mediate excitatory synaptic transmission. AMPAR ion channels exhibit multiple subconductance states that tune neuronal responses to glutamate. GluA4 is the ...AMPA-subtype glutamate receptors (AMPARs) mediate excitatory synaptic transmission. AMPAR ion channels exhibit multiple subconductance states that tune neuronal responses to glutamate. GluA4 is the rarest subunit in the brain but is enriched in interneurons and the cerebellum. Rising evidence points to GluA4 AMPARs in the development of neurological diseases, but the structural mechanisms of GluA4 function remain enigmatic. Here, we show the distinct features of GluA4 that tune AMPAR function. We find that GluA4 AMPARs have a canonical "Y" shaped architecture where local dimer pairs are domain-swapped between the amino terminal domain (NTD) and ligand binding domain (LBD), both of which comprise the extracellular domain. All four LBDs are glutamate bound yet open the GluA4 ion channel by asymmetric hinging in all four channel helices. We observe that the glutamate-saturated LBD has conformational plasticity, which tunes the ion channel gate below. These data provide a framework for understanding channel subconductance, outline the distinct properties of GluA4, expand our understanding of conformational plasticity in AMPARs, and will inform therapeutic design.
History
DepositionJun 24, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 28, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Sep 23, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform 2 of Glutamate receptor 4
B: Isoform 2 of Glutamate receptor 4
C: Isoform 2 of Glutamate receptor 4
D: Isoform 2 of Glutamate receptor 4
H: Voltage-dependent calcium channel gamma-2 subunit
F: Voltage-dependent calcium channel gamma-2 subunit
G: Voltage-dependent calcium channel gamma-2 subunit
E: Voltage-dependent calcium channel gamma-2 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)474,97516
Polymers472,8278
Non-polymers2,1488
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Isoform 2 of Glutamate receptor 4 / GluR-4 / GluR4 / AMPA-selective glutamate receptor 4 / GluR-D / Glutamate receptor ionotropic / AMPA 4 / GluA4


Mass: 95140.234 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gria4, Glur4 / Production host: Homo sapiens (human) / References: UniProt: P19493
#2: Protein
Voltage-dependent calcium channel gamma-2 subunit / Neuronal voltage-gated calcium channel gamma-2 subunit / Stargazin / Transmembrane AMPAR regulatory ...Neuronal voltage-gated calcium channel gamma-2 subunit / Stargazin / Transmembrane AMPAR regulatory protein gamma-2 / TARP gamma-2


Mass: 23066.498 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Cacng2, Stg / Production host: Homo sapiens (human) / References: UniProt: O88602
#3: Chemical
ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C5H9NO4
#4: Chemical
ChemComp-CYZ / CYCLOTHIAZIDE / 3-BICYCLO[2.2.1]HEPT-5-EN-2-YL-6-CHLORO-3,4- DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-7-SULFONAMIDE 1,1 DIOXIDE


Mass: 389.878 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H16ClN3O4S2
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Octameric complex of four GluA4 subunits in complex with four TARP gamma 2 subunits.
Type: COMPLEX / Entity ID: #2, #1 / Source: RECOMBINANT
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.2_5419model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59237 / Symmetry type: POINT
RefinementHighest resolution: 3.89 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00418524
ELECTRON MICROSCOPYf_angle_d0.76525036
ELECTRON MICROSCOPYf_dihedral_angle_d8.4852508
ELECTRON MICROSCOPYf_chiral_restr0.1622800
ELECTRON MICROSCOPYf_plane_restr0.0073064

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