RGD Reference Report - X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. - Rat Genome Database

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X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.

Authors: Sobolevsky, AI  Rosconi, MP  Gouaux, E 
Citation: Sobolevsky AI, etal., Nature. 2009 Dec 10;462(7274):745-56. doi: 10.1038/nature08624. Epub .
RGD ID: 8553832
Pubmed: PMID:19946266   (View Abstract at PubMed)
PMCID: PMC2861655   (View Article at PubMed Central)
DOI: DOI:10.1038/nature08624   (Journal Full-text)

Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
protein tetramerization involved_inIDA 8553832PMID:19946266UniProt 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
AMPA glutamate receptor complex part_ofIDA 8553832PMID:19946266UniProt 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glutamate-gated receptor activity enablesIDA 8553832PMID:19946266UniProt 
identical protein binding enablesIPIUniProtKB:P19491-28553832PMID:19946266IntAct 

Objects Annotated

Genes (Rattus norvegicus)
Gria2  (glutamate ionotropic receptor AMPA type subunit 2)


Additional Information