Mechanism of NMDA receptor channel block by MK-801 and memantine

Xianqiang Song, Morten O. Jensen, Vishwanath Jogini, Richard A. Stein, Chia Hsueh Lee, Hassane S. McHaourab, David E. Shaw, Eric Gouaux

Research output: Contribution to journalArticle

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Abstract

The NMDA (N-methyl-d-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel 1 . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.

Original languageEnglish (US)
Pages (from-to)515-519
Number of pages5
JournalNature
Volume556
Issue number7702
DOIs
StatePublished - Apr 26 2018

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Memantine
Dizocilpine Maleate
Ion Channels
Ions
Molecular Dynamics Simulation
Calcium Channels
Glycine
Glutamic Acid
Alzheimer Disease
Binding Sites
aspartic acid receptor
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Song, X., Jensen, M. O., Jogini, V., Stein, R. A., Lee, C. H., McHaourab, H. S., ... Gouaux, E. (2018). Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature, 556(7702), 515-519. https://doi.org/10.1038/s41586-018-0039-9

Mechanism of NMDA receptor channel block by MK-801 and memantine. / Song, Xianqiang; Jensen, Morten O.; Jogini, Vishwanath; Stein, Richard A.; Lee, Chia Hsueh; McHaourab, Hassane S.; Shaw, David E.; Gouaux, Eric.

In: Nature, Vol. 556, No. 7702, 26.04.2018, p. 515-519.

Research output: Contribution to journalArticle

Song, X, Jensen, MO, Jogini, V, Stein, RA, Lee, CH, McHaourab, HS, Shaw, DE & Gouaux, E 2018, 'Mechanism of NMDA receptor channel block by MK-801 and memantine', Nature, vol. 556, no. 7702, pp. 515-519. https://doi.org/10.1038/s41586-018-0039-9
Song X, Jensen MO, Jogini V, Stein RA, Lee CH, McHaourab HS et al. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature. 2018 Apr 26;556(7702):515-519. https://doi.org/10.1038/s41586-018-0039-9
Song, Xianqiang ; Jensen, Morten O. ; Jogini, Vishwanath ; Stein, Richard A. ; Lee, Chia Hsueh ; McHaourab, Hassane S. ; Shaw, David E. ; Gouaux, Eric. / Mechanism of NMDA receptor channel block by MK-801 and memantine. In: Nature. 2018 ; Vol. 556, No. 7702. pp. 515-519.
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