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-Structure paper
タイトル | Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition. |
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ジャーナル・号・ページ | Nature, Vol. 594, Issue 7863, Page 448-453, Year 2021 |
掲載日 | 2021年5月12日 |
著者 | Jie Yu / Prashant Rao / Sarah Clark / Jaba Mitra / Taekjip Ha / Eric Gouaux / |
PubMed 要旨 | 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. |
リンク | Nature / PubMed:33981040 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.25 - 7.5 Å |
構造データ | EMDB-23283, PDB-7ldd: EMDB-23284, PDB-7lde: EMDB-23285: native AMPA receptor EMDB-23286: native AMPA receptor EMDB-23287: native AMPA receptor EMDB-23288: native AMPA receptor EMDB-23289: EMDB-23290: EMDB-23292, PDB-7lep: |
化合物 | ChemComp-ZK1: ChemComp-R16: ChemComp-OCT: ChemComp-HP6: ChemComp-D10: ChemComp-NAG: ChemComp-D12: ChemComp-C14: ChemComp-DD9: ChemComp-XVD: ChemComp-POV: |
由来 |
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キーワード | MEMBRANE 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 |