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- PDB-7ldd: native AMPA receptor -

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Basic information

Entry
Database: PDB / ID: 7ldd
Titlenative AMPA receptor
Components
  • 11B8 scFv
  • 15F1 Fab heavy chain
  • 15F1 Fab light chain
  • Glutamate receptor
  • Glutamate receptor 1
  • Protein cornichon homolog 2
  • Voltage-dependent calcium channel gamma-8 subunit
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / neurotransmitter / two-fold symmetry / hippocampus / ion-channel / MEMBRANE PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


negative regulation of anterograde synaptic vesicle transport / negative regulation of receptor localization to synapse / Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / Activation of AMPA receptors / COPII-mediated vesicle transport / Synaptic adhesion-like molecules / LGI-ADAM interactions / Unblocking of NMDA receptors, glutamate binding and activation ...negative regulation of anterograde synaptic vesicle transport / negative regulation of receptor localization to synapse / Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / Activation of AMPA receptors / COPII-mediated vesicle transport / Synaptic adhesion-like molecules / LGI-ADAM interactions / Unblocking of NMDA receptors, glutamate binding and activation / Trafficking of GluR2-containing AMPA receptors / cellular response to ammonium ion / axonal spine / Trafficking of AMPA receptors / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / localization within membrane / response to sucrose / regulation of monoatomic ion transmembrane transport / L-type voltage-gated calcium channel complex / myosin V binding / positive regulation of AMPA receptor activity / cellular response to L-glutamate / neuron spine / postsynaptic neurotransmitter receptor diffusion trapping / proximal dendrite / protein phosphatase 2B binding / long-term synaptic depression / regulation of AMPA receptor activity / response to arsenic-containing substance / channel regulator activity / cellular response to dsRNA / ligand-gated calcium channel activity / dendritic spine membrane / regulation of NMDA receptor activity / beta-2 adrenergic receptor binding / cellular response to peptide hormone stimulus / spinal cord development / cellular response to amine stimulus / peptide hormone receptor binding / response to psychosocial stress / response to morphine / perisynaptic space / behavioral response to pain / neuronal cell body membrane / response to lithium ion / AMPA glutamate receptor activity / protein kinase A binding / regulation of receptor recycling / transmission of nerve impulse / neuronal action potential / immunoglobulin binding / adenylate cyclase binding / AMPA glutamate receptor complex / response to electrical stimulus / ionotropic glutamate receptor complex / cellular response to glycine / asymmetric synapse / G-protein alpha-subunit binding / glutamate receptor binding / positive regulation of synaptic transmission / conditioned place preference / regulation of postsynaptic membrane neurotransmitter receptor levels / long-term memory / postsynaptic density, intracellular component / voltage-gated calcium channel activity / response to fungicide / vesicle-mediated transport / glutamate-gated receptor activity / cellular response to brain-derived neurotrophic factor stimulus / positive regulation of synaptic transmission, glutamatergic / synapse assembly / somatodendritic compartment / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / ionotropic glutamate receptor binding / excitatory synapse / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / positive regulation of excitatory postsynaptic potential / dendritic shaft / synaptic membrane / response to cocaine / PDZ domain binding / calcium channel regulator activity / synaptic transmission, glutamatergic / neuromuscular junction / long-term synaptic potentiation / receptor internalization / cerebral cortex development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / regulation of synaptic plasticity / regulation of membrane potential / response to nutrient levels / response to toxic substance / recycling endosome / postsynaptic density membrane / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / small GTPase binding
Similarity search - Function
Voltage-dependent calcium channel, gamma-8 subunit / Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily ...Voltage-dependent calcium channel, gamma-8 subunit / Cornichon / Cornichon, conserved site / Cornichon protein / Cornichon family signature. / Cornichon / : / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
TETRADECANE / DECANE / DODECANE / nonane / HEPTANE / N-OCTANE / HEXADECANE / Chem-XVD / Chem-ZK1 / Glutamate receptor ...TETRADECANE / DECANE / DODECANE / nonane / HEPTANE / N-OCTANE / HEXADECANE / Chem-XVD / Chem-ZK1 / Glutamate receptor / Protein cornichon homolog 2 / Glutamate receptor 1 / Voltage-dependent calcium channel gamma-8 subunit
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYu, J. / Rao, P. / Gouaux, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS038631 United States
Citation
Journal: Nature / Year: 2021
Title: Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition.
Authors: Jie Yu / Prashant Rao / Sarah Clark / Jaba Mitra / Taekjip Ha / Eric Gouaux /
Abstract: AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are ...AMPA-selective glutamate receptors mediate the transduction of signals between the neuronal circuits of the hippocampus. The trafficking, localization, kinetics and pharmacology of AMPA receptors are tuned by an ensemble of auxiliary protein subunits, which are integral membrane proteins that associate with the receptor to yield bona fide receptor signalling complexes. Thus far, extensive studies of recombinant AMPA receptor-auxiliary subunit complexes using engineered protein constructs have not been able to faithfully elucidate the molecular architecture of hippocampal AMPA receptor complexes. Here we obtain mouse hippocampal, calcium-impermeable AMPA receptor complexes using immunoaffinity purification and use single-molecule fluorescence and cryo-electron microscopy experiments to elucidate three major AMPA receptor-auxiliary subunit complexes. The GluA1-GluA2, GluA1-GluA2-GluA3 and GluA2-GluA3 receptors are the predominant assemblies, with the auxiliary subunits TARP-γ8 and CNIH2-SynDIG4 non-stochastically positioned at the B'/D' and A'/C' positions, respectively. We further demonstrate how the receptor-TARP-γ8 stoichiometry explains the mechanism of and submaximal inhibition by a clinically relevant, brain-region-specific allosteric inhibitor.
#1: Journal: Science / Year: 2019
Title: Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM.
Authors: Yan Zhao / Shanshuang Chen / Adam C Swensen / Wei-Jun Qian / Eric Gouaux /
Abstract: Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions of the mammalian brain. AMPA receptors are tetrameric ...Glutamate-gated AMPA receptors mediate the fast component of excitatory signal transduction at chemical synapses throughout all regions of the mammalian brain. AMPA receptors are tetrameric assemblies composed of four subunits, GluA1-GluA4. Despite decades of study, the subunit composition, subunit arrangement, and molecular structure of native AMPA receptors remain unknown. Here we elucidate the structures of 10 distinct native AMPA receptor complexes by single-particle cryo-electron microscopy (cryo-EM). We find that receptor subunits are arranged nonstochastically, with the GluA2 subunit preferentially occupying the B and D positions of the tetramer and with triheteromeric assemblies comprising a major population of native AMPA receptors. Cryo-EM maps define the structure for S2-M4 linkers between the ligand-binding and transmembrane domains, suggesting how neurotransmitter binding is coupled to ion channel gating.
History
DepositionJan 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 30, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 16, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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  • Deposited structure unit
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  • Superimposition on EM map
  • EMDB-23283
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Assembly

Deposited unit
A: Glutamate receptor 1
B: Glutamate receptor
C: Glutamate receptor 1
D: Glutamate receptor
E: Protein cornichon homolog 2
F: Protein cornichon homolog 2
G: Voltage-dependent calcium channel gamma-8 subunit
H: Voltage-dependent calcium channel gamma-8 subunit
I: 11B8 scFv
J: 15F1 Fab light chain
K: 15F1 Fab heavy chain
L: 11B8 scFv
M: 15F1 Fab light chain
N: 15F1 Fab heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)698,54466
Polymers687,25814
Non-polymers11,28652
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: immunoprecipitation
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 4 types, 8 molecules ACBDEFGH

#1: Protein Glutamate receptor 1 / GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / ...GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / AMPA 1 / GluA1


Mass: 101678.969 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P23818
#2: Protein Glutamate receptor


Mass: 98899.883 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: G5E8H1
#3: Protein Protein cornichon homolog 2 / CNIH-2 / Cornichon family AMPA receptor auxiliary protein 2 / Cornichon-like protein


Mass: 18948.420 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: O35089
#4: Protein Voltage-dependent calcium channel gamma-8 subunit / Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein ...Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein gamma-8 / TARP gamma-8


Mass: 43502.938 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q8VHW2

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Antibody , 3 types, 6 molecules ILJMKN

#5: Antibody 11B8 scFv


Mass: 27511.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Escherichia coli (E. coli)
#6: Antibody 15F1 Fab light chain


Mass: 25111.660 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse)
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
#7: Antibody 15F1 Fab heavy chain


Mass: 27975.439 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse)
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)

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Sugars , 2 types, 12 molecules

#8: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 6 / Source method: isolated from a natural source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#14: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 9 types, 40 molecules

#9: Chemical
ChemComp-ZK1 / {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / [[3,4-Dihydro-7-(4-morpholinyl)-2,3-dioxo-6-(trifluorom ethyl)-1(2H)-quinoxalinyl]methyl]phosphonic acid


Mass: 409.254 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H15F3N3O6P / Comment: medication*YM
#10: Chemical ChemComp-R16 / HEXADECANE


Mass: 226.441 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H34
#11: Chemical
ChemComp-OCT / N-OCTANE


Mass: 114.229 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H18
#12: Chemical
ChemComp-HP6 / HEPTANE


Mass: 100.202 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C7H16
#13: Chemical
ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H22
#15: Chemical
ChemComp-D12 / DODECANE


Mass: 170.335 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C12H26
#16: Chemical
ChemComp-C14 / TETRADECANE


Mass: 198.388 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C14H30
#17: Chemical
ChemComp-DD9 / nonane


Mass: 128.255 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H20
#18: Chemical ChemComp-XVD / 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol


Mass: 328.674 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H8ClF3N2O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1GluA1/A2-symmetric-conformation bound to antibody fragmentsCOMPLEX#1-#70MULTIPLE SOURCES
2GluA1/A2-symmetric-conformationCOMPLEX#1-#41NATURAL
311B8 scFvCOMPLEX#51RECOMBINANT
415F1 FabCOMPLEX#6-#71RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Mus musculus (house mouse)10090
23Mus musculus (house mouse)10090
34Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
13Escherichia coli (E. coli)562
24Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)2449148
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 829000 / Symmetry type: POINT

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