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

Author

Listed:
  • 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
    Rockefeller University)

  • Hassane S. Mchaourab

    (Vanderbilt University)

  • David E. Shaw

    (D. E. Shaw Research
    Columbia University)

  • Eric Gouaux

    (Oregon Health & Science University
    Oregon Health & Science University)

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.

Suggested Citation

  • Xianqiang Song & Morten Ø. Jensen & Vishwanath Jogini & Richard A. Stein & Chia-Hsueh Lee & Hassane S. Mchaourab & David E. Shaw & Eric Gouaux, 2018. "Mechanism of NMDA receptor channel block by MK-801 and memantine," Nature, Nature, vol. 556(7702), pages 515-519, April.
    • Handle: RePEc:nat:nature:v:556:y:2018:i:7702:d:10.1038_s41586-018-0039-9
    DOI: 10.1038/s41586-018-0039-9
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    Cited by:

    1. Nami Tajima & Noriko Simorowski & Remy A. Yovanno & Michael C. Regan & Kevin Michalski & Ricardo Gómez & Albert Y. Lau & Hiro Furukawa, 2022. "Development and characterization of functional antibodies targeting NMDA receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Madeleine R. Wilcox & Aparna Nigam & Nathan G. Glasgow & Chamali Narangoda & Matthew B. Phillips & Dhilon S. Patel & Samaneh Mesbahi-Vasey & Andreea L. Turcu & Santiago Vázquez & Maria G. Kurnikova & , 2022. "Inhibition of NMDA receptors through a membrane-to-channel path," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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