Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N-terminal domain.

N-methyl-D-aspartate receptors (NMDARs), neuronal glutamate-gated ion channels, are obligatory heterotetramers composed of GluN1 and GluN2 subunits. Each subunit contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). The GluN2 NTDs form mobile regulatory domains. In contrast, the dynamics of GluN1 NTD and its contribution to NMDAR function remain poorly understood. Here we show that GluN1 NTD is neither static nor functionally silent. Perturbing the conformation of GluN1 NTD affects both receptor gating and pharmacological properties. GluN1 NTD undergoes structural rearrangements that involve hinge bending and large twisting and untwisting motions, allowing for new intra- and intersubunit contacts. GluN1 NTD acts in trans with GluN2 NTD to influence binding of glutamate but, notably, not of GluN1 coagonist glycine. Our work uncovers a dynamic role of GluN1 NTD in controlling NMDAR function through new interdomain allosteric interactions.