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- PDB-7lep: The composite LBD-TMD structure combined from all hippocampal AMP... -

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Basic information

Entry
Database: PDB / ID: 7lep
TitleThe composite LBD-TMD structure combined from all hippocampal AMPAR subtypes at 3.25 Angstrom resolution
Components
  • (Mix of AMPAR subunits (GluA1, GluA3, and ...) x 2
  • Glutamate receptor 2GRIA2
  • Protein cornichon homolog 2
  • Voltage-dependent calcium channel gamma-8 subunit
KeywordsMEMBRANE PROTEIN / Native hippocampal ion channel
Function / homology
Function and homology information


Phase 2 - plateau phase / Phase 0 - rapid depolarisation / negative regulation of receptor localization to synapse / negative regulation of anterograde synaptic vesicle transport / Cargo concentration in the ER / LGI-ADAM interactions / COPII-mediated vesicle transport / Trafficking of AMPA receptors / localization within membrane / neurotransmitter receptor transport, postsynaptic endosome to lysosome ...Phase 2 - plateau phase / Phase 0 - rapid depolarisation / negative regulation of receptor localization to synapse / negative regulation of anterograde synaptic vesicle transport / Cargo concentration in the ER / LGI-ADAM interactions / COPII-mediated vesicle transport / Trafficking of AMPA receptors / localization within membrane / neurotransmitter receptor transport, postsynaptic endosome to lysosome / L-type voltage-gated calcium channel complex / regulation of AMPA receptor activity / neurotransmitter receptor internalization / channel regulator activity / protein phosphatase 2B binding / postsynaptic neurotransmitter receptor diffusion trapping / transmission of nerve impulse / regulation of postsynaptic membrane neurotransmitter receptor levels / calcium channel regulator activity / AMPA glutamate receptor complex / voltage-gated calcium channel activity / glutamate-gated receptor activity / vesicle-mediated transport / dendrite membrane / ionotropic glutamate receptor binding / regulation of membrane potential / positive regulation of synaptic transmission, glutamatergic / dendritic shaft / synaptic transmission, glutamatergic / postsynaptic density membrane / Schaffer collateral - CA1 synapse / postsynaptic membrane / dendritic spine / postsynaptic density / membrane => GO:0016020 / dendrite / glutamatergic synapse / synapse / endoplasmic reticulum membrane
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 / Ionotropic glutamate receptor, metazoa ...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
Similarity search - Domain/homology
TETRADECANE / DECANE / DODECANE / N-OCTANE / Chem-POV / Chem-XVD / Chem-ZK1 / Glutamate receptor / Protein cornichon homolog 2 / Voltage-dependent calcium channel gamma-8 subunit
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.25 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
CitationJournal: 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.
History
DepositionJan 14, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1May 26, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 30, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Mix of AMPAR subunits (GluA1, GluA3, and GluA4)
B: Glutamate receptor 2
C: Mix of AMPAR subunits (GluA1, GluA3, and GluAX)
D: Glutamate receptor 2
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)291,86050
Polymers265,8548
Non-polymers26,00642
Water0
1


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

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Components

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Mix of AMPAR subunits (GluA1, GluA3, and ... , 2 types, 2 molecules AC

#1: Protein Mix of AMPAR subunits (GluA1, GluA3, and GluA4)


Mass: 43650.676 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)
#3: Protein Mix of AMPAR subunits (GluA1, GluA3, and GluAX)


Mass: 43702.637 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse)

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Protein , 3 types, 6 molecules BDEFGH

#2: Protein Glutamate receptor 2 / GRIA2


Mass: 47252.312 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: C9K0Z0
#4: Protein Protein cornichon homolog 2 / CNIH-2 / Cornichon family AMPA receptor auxiliary protein 2 / Cornichon-like protein


Mass: 18755.152 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: O35089
#5: 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: 23242.705 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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Non-polymers , 7 types, 42 molecules

#6: 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 / Fanapanel


Mass: 409.254 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H15F3N3O6P / Comment: antagonist, medication*YM
#7: Chemical...
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC / POPC


Mass: 760.076 Da / Num. of mol.: 30 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#8: Chemical ChemComp-C14 / TETRADECANE / Tetradecane


Mass: 198.388 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30
#9: Chemical ChemComp-D10 / DECANE / Decane


Mass: 142.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22
#10: 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
#11: Chemical ChemComp-OCT / N-OCTANE / Octane


Mass: 114.229 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18
#12: Chemical ChemComp-D12 / DODECANE / Dodecane


Mass: 170.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H26

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Details

Has ligand of interestY

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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: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes
Type: COMPLEX / Details: Bound with MPQX and JNJ55511118 / Entity ID: #1-#5 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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 FIELDBright-field microscopy
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: cryoSPARC / Category: CTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 116710 / Symmetry type: POINT

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