title: Cooperative Dynamics of Intact AMPA and NMDA Glutamate Receptors: Similarities and Subfamily-Specific Differences.
abstract: Ionotropic glutamate receptors (iGluRs) are tetrameric ion channels that mediate excitatory neurotransmission. Recent structures of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors permit a comparative analysis of whole-receptor dynamics for the first time. Despite substantial differences in the packing of their two-domain extracellular region, the two iGluRs share similar dynamics, elucidated by elastic network models. Motions accessible to either structure enable conformational interconversion, such as compression of the AMPA receptor toward the more tightly packed NMDA receptor conformation, which has been linked to allosteric regulation. Pivoting motions coupled to concerted rotations of the transmembrane ion channel are prominent between dimers of distal N-terminal domains in the loosely packed AMPA receptor. The occurrence and functional relevance of these motions is verified by cross-linking experiments designed to probe the computationally predicted distance changes. Together with the identification of hotspot residues acting as mediators of allosteric communication, our data provide a glimpse into the dynamic spectrum of iGluRs.
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Avenue, Suite 3064 BST3, Pittsburgh, PA 15260, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Dutta
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: James
authors.initials: J
authors.lastname: Krieger
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Avenue, Suite 3064 BST3, Pittsburgh, PA 15260, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Nafria
authors.affiliation: Neurobiology Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Greger
authors.affiliation: Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, 3501 Fifth Avenue, Suite 3064 BST3, Pittsburgh, PA 15260, USA. Electronic address: bahar@pitt.edu.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate
keywords: AMPA and NMDA receptors; NTD-LBD coupling; allosteric events; conformational dynamics; crosslinking; effector residues; elastic network models; ionotropic glutamate receptors; mutagenesis; signal transduction