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

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. 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. Here, 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.

Authors:
 [1];  [2];  [2];  [3];  [1];  [3];  [4];  [1]
  1. Oregon Health & Science Univ., Portland, OR (United States)
  2. D. E. Shaw Research, New York, NY (United States)
  3. Vanderbilt Univ., Nashville, TN (United States)
  4. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health
OSTI Identifier:
1435812
Grant/Contract Number:  
R01 NS038631
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 556; Journal Issue: 7702; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Molecular neuroscience; Protein analysis; X-ray crystallography

Citation Formats

Song, Xianqiang, Jensen, Morten Ø., Jogini, Vishwanath, Stein, Richard A., Lee, Chia-Hsueh, Mchaourab, Hassane S., Shaw, David E., and Gouaux, Eric. Mechanism of NMDA receptor channel block by MK-801 and memantine. United States: N. p., 2018. Web. doi:10.1038/s41586-018-0039-9.
Song, Xianqiang, Jensen, Morten Ø., 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. United States. doi:10.1038/s41586-018-0039-9.
Song, Xianqiang, Jensen, Morten Ø., Jogini, Vishwanath, Stein, Richard A., Lee, Chia-Hsueh, Mchaourab, Hassane S., Shaw, David E., and Gouaux, Eric. Wed . "Mechanism of NMDA receptor channel block by MK-801 and memantine". United States. doi:10.1038/s41586-018-0039-9. https://www.osti.gov/servlets/purl/1435812.
@article{osti_1435812,
title = {Mechanism of NMDA receptor channel block by MK-801 and memantine},
author = {Song, Xianqiang and Jensen, Morten Ø. and Jogini, Vishwanath and Stein, Richard A. and Lee, Chia-Hsueh and Mchaourab, Hassane S. and Shaw, David E. and Gouaux, Eric},
abstractNote = {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. 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. Here, 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.},
doi = {10.1038/s41586-018-0039-9},
journal = {Nature (London)},
issn = {0028-0836},
number = 7702,
volume = 556,
place = {United States},
year = {2018},
month = {4}
}

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