title: Molecular dynamics simulations of the ligand-binding domain of the ionotropic glutamate receptor GluR2.
abstract: Ionotropic glutamate receptors are essential for fast synaptic nerve transmission. Recent x-ray structures for the ligand-binding (S1S2) region of the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive receptor have suggested how differences in protein/ligand interactions may determine whether a ligand will behave as a full agonist. We have used multiple molecular dynamics simulations of 2-5 ns duration to explore the structural dynamics of GluR2 S1S2 in the presence and absence of glutamate and in a complex with kainate. Our studies indicate that not only is the degree of domain closure dependent upon interactions with the ligand, but also that protein/ligand interactions influence the motion of the S2 domain with respect to S1. Differences in domain mobility between the three states (apo-S1S2, glutamate-bound, and kainate-bound) are surprisingly clear-cut. We discuss how these changes in dynamics may provide an explanation relating the mechanism of transmission of the agonist-binding event to channel opening. We also show here how the glutamate may adopt an alternative mode of binding not seen in the x-ray structure, which involves a key threonine (T480) side chain flipping into a new conformation. This new conformation results in an altered pattern of hydrogen bonding at the agonist-binding site.
authors.affiliation: Laboratory of Molecular Biophysics, Department of Biochemistry, The University of Oxford, Oxford OX1 3QU, United Kingdom.
authors.forename: Yalini
authors.initials: Y
authors.lastname: Arinaminpathy
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
mesh_terms: D000465:Algorithms; D016633:Apolipoprotein A-II / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007608:Kainic Acid / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000737:chemistry*; D013912:Threonine / Q000737:chemistry; D013997:Time Factors
chemical_list: D016633:Apolipoprotein A-II; D008024:Ligands; D010455:Peptides; D018091:Receptors, AMPA; D013912:Threonine; D018698:Glutamic Acid; C104722:glutamate receptor ionotropic, AMPA 2; D007608:Kainic Acid