title: Comparative dynamics of NMDA- and AMPA-glutamate receptor N-terminal domains.
abstract: 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.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Dutta
authors.forename: Indira H
authors.initials: IH
authors.lastname: Shrivastava
authors.forename: Madhav
authors.initials: M
authors.lastname: Sukumaran
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000494:Allosteric Regulation; D019281:Dimerization; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D018091:Receptors, AMPA / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*
chemical_list: D008024:Ligands; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate