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

Alexander I. Sobolevsky, Michael P. Rosconi, Eric Gouaux

Research output: Contribution to journalArticle

689 Citations (Scopus)

Abstract

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 α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 Å 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.

Original languageEnglish (US)
Pages (from-to)745-756
Number of pages12
JournalNature
Volume462
Issue number7274
DOIs
StatePublished - Dec 10 2009

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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Glutamate Receptors
Ion Channels
X-Rays
Ionotropic Glutamate Receptors
Isoxazoles
Neurobiology
Site-Directed Mutagenesis
Synaptic Transmission
Cysteine
Glutamic Acid
Central Nervous System

ASJC Scopus subject areas

  • General

Cite this

X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. / Sobolevsky, Alexander I.; Rosconi, Michael P.; Gouaux, Eric.

In: Nature, Vol. 462, No. 7274, 10.12.2009, p. 745-756.

Research output: Contribution to journalArticle

Sobolevsky, Alexander I. ; Rosconi, Michael P. ; Gouaux, Eric. / X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. In: Nature. 2009 ; Vol. 462, No. 7274. pp. 745-756.
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