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

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.

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Figure 1: Architecture of homomeric rat GluA2 receptor.
Figure 2: Domain symmetry and architecture.
Figure 3: Transmembrane domain architecture.
Figure 4: Probing intersubunit interfaces in GluA2 AMPA receptors.
Figure 5: Subunit arrangement in NMDA receptors.
Figure 6: Subunit non-equivalence and ‘domain swapping’.
Figure 7: Two-fold to four-fold symmetry transition.
Figure 8: Gating ‘machinery’ accommodates symmetry mismatch.
Figure 9: Closed conformation of the ion channel pore.
Figure 10: Closed state conformations of iGluR and K + channels are similar.
Figure 11: iGluR activation gating.
Figure 12: iGluR desensitization.

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Acknowledgements

We thank the personnel at beamlines 5.0.2, 8.2.1 and 8.2.2 of the Advanced Light Source and at beamline 24-ID-E of the Advanced Photon Source. We also thank T. Homrichhausen for help with cloning and FSEC screening; L. Vaskalis for assistance with illustrations; and Gouaux laboratory members for discussion. M.P.R. was supported by an individual NIH National Research Service Award. This work was supported by the NIH. E.G. is an investigator with the Howard Hughes Medical Institute.

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Correspondence to Eric Gouaux.

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Coordinates and structure factors for GluA2cryst and the GluA2 ligand-binding core complex bound with glutamate, LY404187 and ZK200775 have been deposited with the Protein Data Bank under codes 3KG2 and 3KGC respectively.

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Sobolevsky, A., Rosconi, M. & Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009). https://doi.org/10.1038/nature08624

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