Summary 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.

Zirconium diboride (ZrB 2 ) was densified by pressureless sintering using o4-wt% boron carbide and/or carbon as sintering aids. As-received ZrB 2 with an average particle size of B2 lm could be sintered to B100% density at 19001C using a combination of boron carbide and carbon to react with and remove the surface oxide impurities. Even though particle size reduction increased the oxygen content of the powders from B0.9 wt% for the as-received powder to B2.0 wt%, the reduction in particle size enhanced the sinterability of the powder. Attrition-milled ZrB 2 with an average particle size of o0.5 lm was sintered to nearly full density at 18501C using either boron carbide or a combination of boride carbide and carbon. Regardless of the starting particle size, densification of ZrB 2 was not possible without the removal of oxygen-based impurities on the particle surfaces by a chemical reaction.

NMDA receptors (NMDARs) form glutamate-gated ion channels that have central roles in neuronal communication and plasticity throughout the brain. Dysfunctions of NMDARs are involved in several central nervous system disorders, including stroke, chronic pain and schizophrenia. One hallmark of NMDARs is that their activity can be allosterically regulated by a variety of extracellular small ligands. While much has been learned recently regarding allosteric inhibition of NMDARs, the structural determinants underlying positive allosteric modulation of these receptors remain poorly defined. Here, we show that polyamines, naturally occurring polycations that selectively enhance NMDARs containing the GluN2B subunit, bind at a dimer interface between GluN1 and GluN2B subunit N-terminal domains (NTDs). Polyamines act by shielding negative charges present on GluN1 and GluN2B NTD lower lobes, allowing their close apposition, an effect that in turn prevents NTD clamshell closure. Our work reveals the mechanistic basis for positive allosteric modulation of NMDARs. It provides the first example of an intersubunit binding site in this class of receptors, a discovery that holds promise for future drug interventions.