Unique Conformational Distributions for NMDA Receptor Glycine and Glutamate Ligand-Binding Domains

Abstract

Ionotropic glutamate receptors (iGluRs) mediate communication at most excitatory synapses in the brain. iGluRs are organized into three major families--the AMPA, kainate, and NMDA receptors. NMDA receptors are obligate heteromeric assemblies of glycine- and glutamate-binding subunits. Unexpectedly, crystal structures of the glycine-binding GluN1 and GluN3A ligand binding domains (LBDs) in their apo states reveal open and closed cleft conformations, respectively. Computed conformational free energy landscapes also exhibit minima at both open and closed cleft conformations for apo GluN1 and GluN3A LBDs. The minimum at the closed cleft conformation is preserved for the glycine-bound LBDs. In contrast, the free energy landscapes for the NMDA and AMPA receptor glutamate-binding subunits GluN2A and GluA2 show a shift in the minimum upon glutamate binding. Principal component analysis reveals a spectrum of conformational transitions that differ for the GluN1, GluN3A, GluN2A, and GluA2 LBDs. This variation highlights the structural complexity of signaling by iGluRs.