Comparative Dynamics of NMDA- and AMPA-Glutamate Receptor N-Terminal Domains

Ionotropic glutamate receptors (iGluRs) harbor two extracellular domains: the membrane-proximal ligand-binding domain (LBD) and the distal N-terminal domain (NTD). These are involved in signal sensing: the LBD binds L-glutamate, which activates the receptor channel. Ligand binding to the NTD modulates channel function in the NMDA receptor subfamily of iGluRs, which has not been observed for the AMPAR subfamily to date. Structural data suggest that AMPAR NTDs are packed into tight dimers and have lost their signaling potential. Here, we assess NTD dynamics from both subfamilies, using a variety of computational tools. We describe the conformational motions that underly NMDAR NTD allosteric signaling. Unexpectedly, AMPAR NTDs are capable of undergoing similar dynamics; although dimerization imposes restrictions, the two subfamilies sample similar, interconvertible conformational subspaces. Finally, we solve the crystal structure of AMPAR GluA4 NTD, and combined with molecular dynamics simulations, we characterize regions pivotal for an as-yet-unexplored dynamic spectrum of AMPAR NTDs. ⺠Crystal structure newly resolved for AMPAR GluA4 N-terminal domain (NTD) ⺠Dynamics underlying NMDA NR2B NTD allostery ⺠Similar global dynamics between AMPA- and NMDA-receptor NTDs ⺠Critical role of dimer interface contacts for GluA3 NTD allostery