Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Nami Tajima, Erkan Karakas, Timothy Grant, Noriko Simorowski, Ruben Diaz-Avalos, Nikolaus Grigorieff () and Hiro Furukawa ()
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Nami Tajima: Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor
Erkan Karakas: Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor
Timothy Grant: Janelia Research Campus, Howard Hughes Medical Institute
Noriko Simorowski: Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor
Ruben Diaz-Avalos: Janelia Research Campus, Howard Hughes Medical Institute
Nikolaus Grigorieff: Janelia Research Campus, Howard Hughes Medical Institute
Hiro Furukawa: Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor

Nature, 2016, vol. 534, issue 7605, 63-68

Abstract: Abstract The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1–GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1–GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.

Date: 2016
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DOI: 10.1038/nature17679

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