TY - JOUR
T1 - Mechanism of NMDA receptor channel block by MK-801 and memantine
AU - Song, Xianqiang
AU - Jensen, Morten O.
AU - Jogini, Vishwanath
AU - Stein, Richard A.
AU - Lee, Chia Hsueh
AU - McHaourab, Hassane S.
AU - Shaw, David E.
AU - Gouaux, Eric
N1 - Funding Information:
Acknowledgements We thank L. Vaskalis and H. Owen for manuscript preparation, Gouaux laboratory members, S. Piana and M. Eastwood for discussions, and the Berkeley Center for Structural Biology (5.0.2) and the Advanced Photon Source (24ID-C and 24ID-E) for assistance with data collection. This work was supported by the National Institutes of Health (R01 NS038631). E.G. is an investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© 2018 Macmillan Publishers Ltd., part of Springer Nature.
PY - 2018/4/26
Y1 - 2018/4/26
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-018-0039-9
DO - 10.1038/s41586-018-0039-9
M3 - Article
C2 - 29670280
AN - SCOPUS:85046013357
SN - 0028-0836
VL - 556
SP - 515
EP - 519
JO - Nature
JF - Nature
IS - 7702
ER -