On mechanism of allosteric modulation of NMDA receptor via amino-terminal domains

A possible mechanism of action of the allosteric modulators of NMDA (N-methyl-d-aspartate) receptors is proposed that involves the stabilization of the twisted closed-clamshell configuration of the amino-terminal domains of GluN1 and GluN2B subunits by negative modulators while positive modulators stabilize a roughly parallel tight arrangement of these domains. These respective motions may play an important role in the transition between the open-channel and closed-channel states of the receptor. In addition, some features of the negative modulator binding site found by means of the molecular dynamics study and pocket analysis can be used in the rational design of the allosteric NMDA receptor modulators.

► Negative NMDA receptor modulators stabilize twisted arrangement of N-terminal domains.
► Molecular dynamics reveals different behavior of modulator-bound and unbound states.
► Modulator-induced subunit motions may affect NMDA receptor activation/inactivation.
► Dynamic model of modulator pocket could support design of novel receptor modulators.