Proposed mechanism for the conformational switch in full-length tetrameric GluN1/GluN2B receptor: inter-dimer rolling in the ABD layer is coupled to entry of the NTD layer in its active state. The positive allosteric modulator spermine, which binds the interface between GluN1 and GluN2B NTD lower lobes, enhances receptor activity by stabilizing the NTD compact form and therefore rolling. Conversely, the negative allosteric modulators zinc and ifenprodil inhibit receptor activity by stabilizing an expanded form of the NTDs (lower lobes further apart) thus preventing rolling. The rolling motion facilitates pore opening by acting on the ABD-TMD connecting linkers 