title: Mechanism of NMDA Receptor Inhibition and Activation.
abstract: N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
authors.affiliation: Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Shujia
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Stein
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, 2730 SW Moody Ave, Portland, OR 97201, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Yoshioka
authors.affiliation: Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Chia-Hsueh
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: April
authors.initials: A
authors.lastname: Goehring
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Hassane S
authors.initials: HS
authors.lastname: Mchaourab
authors.affiliation: Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Electronic address: gouauxe@ohsu.edu.
authors.forename: Eric
authors.initials: E
authors.lastname: Gouaux
mesh_terms: D000818:Animals; D020285:Cryoelectron Microscopy; D004578:Electron Spin Resonance Spectroscopy; D008958:Models, Molecular; D000072417:Protein Domains; D021122:Protein Subunits / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000737:chemistry*; D029867:Xenopus Proteins / Q000737:chemistry*; D014982:Xenopus laevis
chemical_list: D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D029867:Xenopus Proteins