Characterization of NMDA receptor Allostery modulation

NMDA receptors are subject to numerous endogenous and exogenous allosteric regulations, which are essential for their complex pathophysiological functions in the brain, and serve as a basis for therapeutic targeting. However, the structural basis of many of these allosteric mechanisms remains unclear. In this study, we first utilized AlphaFold to predict the structural conformations of different NMDA receptor subtypes. Subsequent comparative analyses with experimentally resolved protein structures, coupled with validation using disulfide bond formation, revealed the high precision of these computational predictions. Based on these structures, we systematically investigated the allosteric regulation of NMDA receptors using RoseTTAFold-All-Atom. Our findings elucidated the binding sites of several allosteric modulators across different NMDA receptor subtypes and identified the key amino acids required for binding. These results reveal the structural basis of NMDA receptor allosteric regulation, providing new insights into its physiological and pathological roles, and offering potential avenues for drug development.