NMDA receptor structures reveal subunit arrangement and pore architecture

Chia Hsueh Lee, Wei Lü, Jennifer Carlisle Michel, April Goehring, Juan Du, Xianqiang Song, Eric Gouaux

Research output: Contribution to journalArticle

287 Scopus citations

Abstract

N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer. Despite the importance of the NMDA receptor in the development and function of the brain, a molecular structure of an intact receptor has remained elusive. Here we present X-ray crystal structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a â ̂1/4twofold symmetric arrangement of ion channel pore loops. These structures provide new insights into the architecture, allosteric coupling and ion channel function of NMDA receptors.

Original languageEnglish (US)
Pages (from-to)191-197
Number of pages7
JournalNature
Volume511
Issue number7508
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • General

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    Lee, C. H., Lü, W., Michel, J. C., Goehring, A., Du, J., Song, X., & Gouaux, E. (2014). NMDA receptor structures reveal subunit arrangement and pore architecture. Nature, 511(7508), 191-197. https://doi.org/10.1038/nature13548