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Structure paper

TitleHippocampal AMPA receptor assemblies and mechanism of allosteric inhibition.
Journal, issue, pagesNature, Vol. 594, Issue 7863, Page 448-453, Year 2021
Publish dateMay 12, 2021
AuthorsJie Yu / Prashant Rao / Sarah Clark / Jaba Mitra / Taekjip Ha / Eric Gouaux /
PubMed AbstractAMPA-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.
External linksNature / PubMed:33981040 / PubMed Central
MethodsEM (single particle)
Resolution3.25 - 7.5 Å
Structure data

23283

7ldd

EMDB-23283, PDB-7ldd:
native AMPA receptor
Method: EM (single particle) / Resolution: 3.4 Å

23284

7lde

EMDB-23284, PDB-7lde:
native AMPA receptor
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-23285: native AMPA receptor
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-23286: native AMPA receptor
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-23287: native AMPA receptor
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-23288: native AMPA receptor
Method: EM (single particle) / Resolution: 6.5 Å

EMDB-23289:
native AMPA receptor
Method: EM (single particle) / Resolution: 5.1 Å

EMDB-23290:
native AMPA receptor
Method: EM (single particle) / Resolution: 7.5 Å

23292

7lep

EMDB-23292, PDB-7lep:
The composite LBD-TMD structure combined from all hippocampal AMPAR subtypes at 3.25 Angstrom resolution
Method: EM (single particle) / Resolution: 3.25 Å

Chemicals

ChemComp-ZK1:
{[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / antagonist, medication*YM / Fanapanel

ChemComp-R16:
HEXADECANE / Hexadecane

ChemComp-OCT:
N-OCTANE / Octane

ChemComp-HP6:
HEPTANE / Heptane

ChemComp-D10:
DECANE / Decane

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-D12:
DODECANE / Dodecane

ChemComp-C14:
TETRADECANE / Tetradecane

ChemComp-DD9:
nonane / Nonane

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

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

Source
  • mus musculus (house mouse)
  • Mouse (mice)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / neurotransmitter / two-fold symmetry / hippocampus / ion-channel / MEMBRANE PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / glycosylation / Native hippocampal ion channel

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