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

Xianqiang Song, Morten Ø. Jensen, Vishwanath Jogini, Richard A. Stein, Chia-Hsueh Lee, Hassane S. Mchaourab, David E. Shaw () and Eric Gouaux ()
Additional contact information
Xianqiang Song: Oregon Health & Science University
Morten Ø. Jensen: D. E. Shaw Research
Vishwanath Jogini: D. E. Shaw Research
Richard A. Stein: Vanderbilt University
Chia-Hsueh Lee: Oregon Health & Science University
Hassane S. Mchaourab: Vanderbilt University
David E. Shaw: D. E. Shaw Research
Eric Gouaux: Oregon Health & Science University

Nature, 2018, vol. 556, issue 7702, 515-519

Abstract: 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 channel1. 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.

Date: 2018
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DOI: 10.1038/s41586-018-0039-9

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