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.
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Electron Microscopy Data Bank
Protein Data Bank
Atomic coordinates and structure factor for the apo-GluN1b–GluN2B ATD is deposited in the Protein Data Bank under the accession code 5B3J; the cryo-EM coordinates are deposited under the accession codes 5FXG, 5FXH, 5FXI, 5FXJ and 5FXK. The cryo-EM maps are deposited in EMDB under accession codes EMD-3352, EMD-3353, EMD-3354, EMD-3355 and EMD-3356.
We thank staff at the 23-ID beamlines at the Advanced Photon System in the Argonne National Laboratory. We are grateful to Z. Yu, C. Hong and R. Huang at the Janelia Research Center/HHMI EM facility for their support. This work was supported by the National Institutes of Health (MH085926 and GM105730), the Stanley Institute of Cognitive Genomics, Burroughs Wellcome Fund Collaborative Research Travel Grant, the Robertson Research Fund of Cold Spring Harbor Laboratory (all to H.F.), Japan Society for the Promotion of Science (to N.T.) and the Visiting Scientist program of the Janelia Research Center to allow H.F. to conduct cryo-EM work.
Extended data figures
This video shows a morph of the GluN1b-GluN2B NMDA receptor structure from ‘non-active state 2’ to ‘active state’ as viewed from the top (left) and side (right). The linkers between the LBD and the TMD except the LBD-M3 linkers are omitted for clarity. The GluN1 (α), GluN1 (β), GluN2B (α) and GluN2B (β) subunits are colored in red, orange, blue and cyan, respectively. The first ordered residues on the linker between the M3 helices on TMD and the LBD in the active state structure (GluN1b Arg 684 and GluN2B Glu 658) are shown as spheres. Note that the TMD of GluN1b-GluN2B NMDA receptor in the ‘active’ state was not well resolved, and that the TMD shown in this video is that of GluN1b-GluN2B NMDA receptor in ‘non-active state 2.’
This video shows a morph of the GluN1b-GluN2B NMDA receptor structure from the ‘non-active state 2’ to the ‘inhibited’ state by ifenprodil (PDB ID: 4PE5) as viewed from the top (left) and side (right). The GluN1 (α), GluN1 (β), GluN2B (α) and GluN2B (β) subunits are colored in red, orange, blue and cyan, respectively. TMD of the GluN1b-GluN2B NMDA receptor in the ‘inhibited’ state was replaced with the TMD of the GluN1b-GluN2B NMDA receptor in the ‘non-active 2’ state. Ifenprodil is shown as green spheres.
About this article
Nature Reviews Neuroscience (2017)