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- EMDB-23292: The composite LBD-TMD structure combined from all hippocampal AMP... -

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Basic information

Entry
Database: EMDB / ID: EMD-23292
TitleThe composite LBD-TMD structure combined from all hippocampal AMPAR subtypes at 3.25 Angstrom resolution
Map data
Sample
  • Complex: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes
    • Protein or peptide: x 5 types
  • Ligand: x 7 types
KeywordsNative hippocampal ion channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / COPII-mediated vesicle transport / LGI-ADAM interactions / Trafficking of AMPA receptors / localization within membrane / L-type voltage-gated calcium channel complex / regulation of AMPA receptor activity / channel regulator activity ...Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / COPII-mediated vesicle transport / LGI-ADAM interactions / Trafficking of AMPA receptors / localization within membrane / L-type voltage-gated calcium channel complex / regulation of AMPA receptor activity / channel regulator activity / AMPA glutamate receptor complex / regulation of postsynaptic membrane neurotransmitter receptor levels / vesicle-mediated transport / dendritic shaft / regulation of membrane potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / calcium channel regulator activity / synaptic transmission, glutamatergic / postsynaptic density membrane / Schaffer collateral - CA1 synapse / calcium channel activity / dendritic spine / postsynaptic membrane / postsynaptic density / dendrite / endoplasmic reticulum membrane / glutamatergic synapse
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 / 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 / Protein cornichon homolog 2 / Voltage-dependent calcium channel gamma-8 subunit
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsYu J / Rao P
Funding support United States, 1 items
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, 2021-
Header (metadata) releaseMay 12, 2021-
Map releaseMay 12, 2021-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.16
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.16
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7lep
  • Surface level: 0.16
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23292.png

Downloads & links

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Map

FileDownload / File: emd_23292.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 400 pix.
= 441.4 Å		1.1 Å/pix.
x 400 pix.
= 441.4 Å		1.1 Å/pix.
x 400 pix.
= 441.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1035 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.156 / Movie #1: 0.16
Minimum - Maximum-0.78660184 - 1.1914166
Average (Standard dev.)-0.0003990681 (±0.02026142)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 441.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.10351.10351.1035
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z441.400441.400441.400
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.7871.191-0.000

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Supplemental data

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Sample components

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Entire : Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes

EntireName: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes
Components
  • Complex: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes
    • Protein or peptide: Mix of AMPAR subunits (GluA1, GluA3, and GluA4)
    • Protein or peptide: Glutamate receptor 2
    • Protein or peptide: Mix of AMPAR subunits (GluA1, GluA3, and GluAX)
    • Protein or peptide: Protein cornichon homolog 2
    • Protein or peptide: Voltage-dependent calcium channel gamma-8 subunit
  • Ligand: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: TETRADECANE
  • Ligand: DECANE
  • Ligand: 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol
  • Ligand: N-OCTANE
  • Ligand: DODECANE

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Supramolecule #1: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes

SupramoleculeName: Composite LBD-TMD complex from the combined hippocampal AMPAR subtypes
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 / Details: Bound with MPQX and JNJ55511118
Source (natural)Organism: Mus musculus (house mouse)

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

MacromoleculeName: Mix of AMPAR subunits (GluA1, GluA3, and GluA4) / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 43.650676 KDa
SequenceString: TAAVTTIAEA PYVMLKKNAA AAEGNAAYEG YCVALAAEIA KHAGAAYAAA IVADGKYGAR DAATKAWNGM VGELVYGRAA AAAAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFS(UNK) (UNK)(UNK)(UNK) ...String:
TAAVTTIAEA PYVMLKKNAA AAEGNAAYEG YCVALAAEIA KHAGAAYAAA IVADGKYGAR DAATKAWNGM VGELVYGRAA AAAAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFS(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)NEF GIFNSLWFSL GAFMQQGCDI SPRSLSG RI VGGVWWFFTL IIISSYTANL AAFLTVERMV SPIESAEDLA KQTEIAYGTL AAGSTKEFFR RSKIAVAAKM WAYMASAE P SVFAATTAAG AARVRKAKGK AAALLESTMN EYIEQRKPCD TMKVGGNLDS KGYGAATPKG SALRAPVNLA VLKLAEQGA LDKLKNKWWY DKGECGAAAA ASKAKTSALS LSNVAGVFYI LAGGLGLAMA VALIEFCYK

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Macromolecule #2: Glutamate receptor 2

MacromoleculeName: Glutamate receptor 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 47.252312 KDa
SequenceString: VVTTILESPY VMMKKNHEML EGNERYEGYC VDLAAEIAKH CGFKYKLTIV GDGKYGARDA DTKIWNGMVG ELVYGKADIA IAPLTITLV REEVIDFSKP FMSLGISIMI KKPQKSKPGV FSFLDPLAYE IWMCIVFAYI GVSVVLFLVS RFSPYEWHTE E FEDGRETQ ...String:
VVTTILESPY VMMKKNHEML EGNERYEGYC VDLAAEIAKH CGFKYKLTIV GDGKYGARDA DTKIWNGMVG ELVYGKADIA IAPLTITLV REEVIDFSKP FMSLGISIMI KKPQKSKPGV FSFLDPLAYE IWMCIVFAYI GVSVVLFLVS RFSPYEWHTE E FEDGRETQ SSESTNEFGI FNSLWFSLGA FMRQGCDISP RSLSGRIVGG VWWFFTLIII SSYTANLAAF LTVERMVSPI ES AEDLSKQ TEIAYGTLDS GSTKEFFRRS KIAVFDKMWT YMRSAEPSVF VRTTAEGVAR VRKSKGKYAY LLESTMNEYI EQR KPCDTM KVGGNLDSKG YGIATPKGSS LGNAVNLAVL KLNEEGLLDK LKNKWWYDKG ECGSGGGDSK EKTSALSLSN VAGV FYILV GGLGLAMLVA LIEFCYKSR

UniProtKB: Glutamate receptor

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Macromolecule #3: Mix of AMPAR subunits (GluA1, GluA3, and GluAX)

MacromoleculeName: Mix of AMPAR subunits (GluA1, GluA3, and GluAX) / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 43.702637 KDa
SequenceString: TAVVTTILED PYVMAKKNAA AAEGNAAYEG YCVALAAEIA KHAAYAYAAA IVADGKYGAR DAATKAWNGM VGELVYGAAD AAAAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFS(UNK) (UNK)(UNK)(UNK) ...String:
TAVVTTILED PYVMAKKNAA AAEGNAAYEG YCVALAAEIA KHAAYAYAAA IVADGKYGAR DAATKAWNGM VGELVYGAAD AAAAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSVVLFL VSRFS(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)NEFG IFNSLWFSLG AFMQQGCDIS PRSLSGRIVG G VWWFFTLI IISSYTANLA AFLTVERMVS PIESAEDLAK QTEIAYGTLA AGSTKEFFRR SKIAVAAKMW AYMASAEPSV FA ATTAAGA ARVRKAKGKA AALLESTMNE YIEQRKPCDT MKVGGNLDSK GYGAATPKGS ALRAPVNLAV LKLAEQGALD KLK AKWWYD KGECGAAAAA SKDKTSALSL SNVAGVFYIL AGGLGLAMAV ALIEFCYK

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Macromolecule #4: Protein cornichon homolog 2

MacromoleculeName: Protein cornichon homolog 2 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 18.755152 KDa
SequenceString:
AFTFAAFCYM LTLVLCASLI FFVIWHIIAF DELRTDFKNP IDQGNPARAR ERLKNIERIC CLLRKLVVPE YSIHGLFCLM FLCAAEWVT LGLNIPLLFT HLWRYFHRPA DGSEVMYDAV SIMNADILNY CQKESWCKLA FYLLSFFYYL YSMVYTLVSF

UniProtKB: Protein cornichon homolog 2

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Macromolecule #5: Voltage-dependent calcium channel gamma-8 subunit

MacromoleculeName: Voltage-dependent calcium channel gamma-8 subunit / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.242705 KDa
SequenceString: VQVLLTTIGA FSAFGLMTIA ISTDYWLYTR ALICNTTNLT AGDDGPPHRG GSGSSEKKDP GGLTHSGLWR ICCLEGLKRG VCVKINHFP EDTDYDHDSA EYLLRVVRAS SIFPILSAIL LLLGGVCVAA SRVYKSKRNI ILGAGILFVA AGLSNIIGVI V YISANAGE ...String:
VQVLLTTIGA FSAFGLMTIA ISTDYWLYTR ALICNTTNLT AGDDGPPHRG GSGSSEKKDP GGLTHSGLWR ICCLEGLKRG VCVKINHFP EDTDYDHDSA EYLLRVVRAS SIFPILSAIL LLLGGVCVAA SRVYKSKRNI ILGAGILFVA AGLSNIIGVI V YISANAGE PGPKRDEEKK NHYSYGWSFY FGGLSFILAE VIGVLAVNIY IERSREA

UniProtKB: Voltage-dependent calcium channel gamma-8 subunit

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Macromolecule #6: {[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: 6 / 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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Macromolecule #7: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 7 / Number of copies: 30 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #8: TETRADECANE

MacromoleculeName: TETRADECANE / type: ligand / ID: 8 / Number of copies: 1 / Formula: C14
Molecular weightTheoretical: 198.388 Da
Chemical component information

ChemComp-C14:
TETRADECANE

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Macromolecule #9: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 9 / Number of copies: 1 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #10: 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol

MacromoleculeName: 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol
type: ligand / ID: 10 / Number of copies: 2 / Formula: XVD
Molecular weightTheoretical: 328.674 Da
Chemical component information

ChemComp-XVD:
6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol

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Macromolecule #11: N-OCTANE

MacromoleculeName: N-OCTANE / type: ligand / ID: 11 / Number of copies: 2 / Formula: OCT
Molecular weightTheoretical: 114.229 Da
Chemical component information

ChemComp-OCT:
N-OCTANE

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Macromolecule #12: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 12 / Number of copies: 2 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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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

BufferpH: 8
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k 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: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
In silico model: The LBD-TMD GluA1/GluA2 hippocampal AMPAR complex
Details: We used the LBD-TMD GluA1/GluA2 model as the initial template.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 116710
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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