Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Tajima, Nami; Karakas, Erkan; Grant, Timothy; Simorowski, Noriko; Diaz-Avalos, Ruben; Grigorieff, Nikolaus; Furukawa, Hiro

doi:10.1038/nature17679

Activation of NMDA receptors and the mechanism of inhibition by ifenprodil

Journal Article · Mon May 02 00:00:00 EDT 2016 · Nature (London)

DOI:https://doi.org/10.1038/nature17679· OSTI ID:1352281

Tajima, Nami ^[1]; Karakas, Erkan ^[1]; Grant, Timothy ^[2]; Simorowski, Noriko ^[1]; Diaz-Avalos, Ruben ^[2]; Grigorieff, Nikolaus ^[2]; Furukawa, Hiro ^[1]

Cold Spring Harbor Lab., NY (United States)
Howard Hughes Medical Inst., Ashburn, VA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Burroughs Wellcome Fund Collaborative Research Travel Grant; Japan Society for the Promotion of Science; National Institutes of Health; Robertson Research Fund of Cold Spring Harbor Laboratory; Stanley Institute of Cognitive Genomics; Visiting Scientist program of the Janelia Research Center

OSTI ID:: 1352281

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7605 Vol. 534; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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