title: Structure, Dynamics, and Allosteric Potential of Ionotropic Glutamate Receptor N-Terminal Domains.
abstract: Ionotropic glutamate receptors (iGluRs) are tetrameric cation channels that mediate synaptic transmission and plasticity. They have a unique modular architecture with four domains: the intracellular C-terminal domain (CTD) that is involved in synaptic targeting, the transmembrane domain (TMD) that forms the ion channel, the membrane-proximal ligand-binding domain (LBD) that binds agonists such as L-glutamate, and the distal N-terminal domain (NTD), whose function is the least clear. The extracellular portion, comprised of the LBD and NTD, is loosely arranged, mediating complex allosteric regulation and providing a rich target for drug development. Here, we briefly review recent work on iGluR NTD structure and dynamics, and further explore the allosteric potential for the NTD in AMPA-type iGluRs using coarse-grained simulations. We also investigate mechanisms underlying the established NTD allostery in NMDA-type iGluRs, as well as the fold-related metabotropic glutamate and GABAB receptors. We show that the clamshell motions intrinsically favored by the NTD bilobate fold are coupled to dimeric and higher-order rearrangements that impact the iGluR LBD and ultimately the TMD. Finally, we explore the dynamics of intact iGluRs and describe how it might affect receptor operation in a synaptic environment.
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: James
authors.initials: J
authors.lastname: Krieger
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, UK. Electronic address: ig@mrc-lmb.cam.ac.uk.
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
mesh_terms: D000494:Allosteric Regulation; D019281:Dimerization; D056004:Molecular Dynamics Simulation; D009038:Motion; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018091:Receptors, AMPA; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate