title: The low binding affinity of D-serine at the ionotropic glutamate receptor GluD2 can be attributed to the hinge region.
abstract: Ionotropic glutamate receptors (iGluRs) are responsible for most of the fast excitatory communication between neurons in our brain. The GluD2 receptor is a puzzling member of the iGluR family: It is involved in synaptic plasticity, plays a role in human diseases, e.g. ataxia, binds glycine and D-serine with low affinity, yet no ligand has been discovered so far that can activate its ion channel. In this study, we show that the hinge region connecting the two subdomains of the GluD2 ligand-binding domain is responsible for the low affinity of D-serine, by analysing GluD2 mutants with electrophysiology, isothermal titration calorimetry and molecular dynamics calculations. The hinge region is highly variable among iGluRs and fine-tunes gating activity, suggesting that in GluD2 this region has evolved to only respond to micromolar concentrations of D-serine.
authors.affiliation: Department of Biochemistry I - Receptor Biochemistry, Ruhr University Bochum, Universitätsstraße 150, 44780 Bochum, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tapken
authors.affiliation: Department of Biochemistry I - Receptor Biochemistry, Ruhr University Bochum, Universitätsstraße 150, 44780 Bochum, Germany.|Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Thomas Bielefeldt
authors.initials: TB
authors.lastname: Steffensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Leth
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Lise Baadsgaard
authors.initials: LB
authors.lastname: Kristensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gerbola
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Flemming Steen
authors.initials: FS
authors.lastname: Jørgensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark.
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D000072417:Protein Domains; D051381:Rats; D017470:Receptors, Glutamate / Q000737:chemistry* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014981:Xenopus
chemical_list: D050505:Mutant Proteins; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C107913:glutamate receptor delta 2; D012694:Serine