Nmda And Ampa Receptor Ligand-Binding Domains Exhibit Subtype-Specific Conformational Propensities

The NMDA receptor family of ionotropic glutamate receptors (iGluRs) is formed by assemblies of GluN1, GluN2, and GluN3 subunits. GluN1 and GluN3 bind glycine, whereas GluN2 binds glutamate. Crystal structures of the GluN1 and GluN3A ligand-binding domains (LBDs) in their apo states reveal open- and closed-cleft conformations, respectively. Computed conformational free energy landscapes for GluN1, GluN2A, and GluN3A LBDs reveal that the apo-state LBDs sample both open- and closed-cleft conformations, suggesting a conformational selection mechanism for agonist binding. By contrast, free energy landscapes for the AMPA receptor GluA2 LBD suggest an induced-fit mechanism for glutamate binding. Principal component analysis reveals a spectrum of large-scale conformational transisitions that are different for the GluN1, GluN2A, GluN3A, and GluA2 LBDs. This diversity in modes of motion highlights the dynamic complexity inherent in glutamate receptor ion channels.