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

By A. Sobolevsky, Michael P. Rosconi, Eric Gouaux. Nature, 2009

990 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/759878a4d283b04d52d845a3a1f0a8a9fc59af18

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Citations in the corpus

Electrical and synaptic integration of glioma into neural circuits (2019, positive): “To generate dominant negative GluA2 subunits of AMPA receptor we carried out two amino acid substitutions in the pore region: Methionine to Arginine (M/R: 606), and Glutamine to Arginine (Q/R: 607); AMPA receptors that incorporate this subunit are non-conducting 54 .”
RCSB Protein Data Bank: Enabling biomedical research and drug discovery (2019, background): “66 Beginning in 2009 with publication of the MX structure of GluA2 AMPA receptor (PDB 3kg2), 67 work in this area has moved rapidly.”
Handbook of ion channels (2015, background): “Recent crystal structures, however, have shown that this is not always the case; for instance, the ligandbinding domains (LBDs) of ionotropic glutamate receptors are arranged as dimers of dimers and only show a twofold symmetry in spite of being homotetramers (93).”
A glimpse of structural biology through X-ray crystallography. (2014, background): “Crystal structure of the homotetrameric AMPA-type GluA2 receptor bound to a competitive antagonist revealed a closed conformation, with a 2-fold symmetry in the extracellular domain and a 4-fold symmetry in the membranespanning ion channel domain (Figure 4D) (Sobolevsky et al., 2009).”