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

250 Citations (Scopus)

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

Fingerprint

Ion Channels
Magnesium
Dizocilpine Maleate
Xenopus laevis
Molecular Structure
Glycine
Glutamic Acid
X-Rays
aspartic acid receptor
Ions
Ligands
Membranes
Brain

ASJC Scopus subject areas

  • General

Cite this

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

NMDA receptor structures reveal subunit arrangement and pore architecture. / Lee, Chia Hsueh; Lü, Wei; Michel, Jennifer Carlisle; Goehring, April; Du, Juan; Song, Xianqiang; Gouaux, Eric.

In: Nature, Vol. 511, No. 7508, 2014, p. 191-197.

Research output: Contribution to journalArticle

Lee, CH, Lü, W, Michel, JC, Goehring, A, Du, J, Song, X & Gouaux, E 2014, 'NMDA receptor structures reveal subunit arrangement and pore architecture', Nature, vol. 511, no. 7508, pp. 191-197. https://doi.org/10.1038/nature13548
Lee CH, Lü W, Michel JC, Goehring A, Du J, Song X et al. NMDA receptor structures reveal subunit arrangement and pore architecture. Nature. 2014;511(7508):191-197. https://doi.org/10.1038/nature13548
Lee, Chia Hsueh ; Lü, Wei ; Michel, Jennifer Carlisle ; Goehring, April ; Du, Juan ; Song, Xianqiang ; Gouaux, Eric. / NMDA receptor structures reveal subunit arrangement and pore architecture. In: Nature. 2014 ; Vol. 511, No. 7508. pp. 191-197.
@article{c5b5b316391d458a98dc19174f235e8b,
title = "NMDA receptor structures reveal subunit arrangement and pore architecture",
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 {\^a} ̂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.",
author = "Lee, {Chia Hsueh} and Wei L{\"u} and Michel, {Jennifer Carlisle} and April Goehring and Juan Du and Xianqiang Song and Eric Gouaux",
year = "2014",
doi = "10.1038/nature13548",
language = "English (US)",
volume = "511",
pages = "191--197",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7508",

}

TY - JOUR

T1 - NMDA receptor structures reveal subunit arrangement and pore architecture

AU - Lee, Chia Hsueh

AU - Lü, Wei

AU - Michel, Jennifer Carlisle

AU - Goehring, April

AU - Du, Juan

AU - Song, Xianqiang

AU - Gouaux, Eric

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84904199124&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904199124&partnerID=8YFLogxK

U2 - 10.1038/nature13548

DO - 10.1038/nature13548

M3 - Article

VL - 511

SP - 191

EP - 197

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7508

ER -