title: The Structure of a High-Affinity Kainate Receptor: GluK4 Ligand-Binding Domain Crystallized with Kainate.
abstract: Ionotropic glutamate receptors play a key role in fast neurotransmission in the CNS and have been linked to several neurological diseases and disorders. One subfamily is the kainate receptors, which are grouped into low-affinity (GluK1-3) and high-affinity (GluK4-5) receptors based on their affinity for kainate. Although structures of the ligand-binding domain (LBD) of all low-affinity kainate receptors have been reported, no structures of the high-affinity receptor subunits are available. Here, we present the X-ray structure of GluK4-LBD with kainate at 2.05 Å resolution, together with thermofluor and radiolabel binding affinity data. Whereas binding-site residues in GluK4 are most similar to the AMPA receptor subfamily, the domain closure and D1-D2 interlobe contacts induced by kainate are similar to the low-affinity kainate receptor GluK1. These observations provide a likely explanation for the high binding affinity of kainate at GluK4-LBD.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Kristensen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, 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 Ø, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Møllerud
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, Denmark.
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, Denmark.
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, 2100 Copenhagen Ø, Denmark. Electronic address: jsk@sund.ku.dk.
authors.forename: Jette Sandholm
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D016367:Baculoviridae / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015870:Gene Expression; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D007608:Kainic Acid / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D018092:Kainic Acid Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061987:Sf9 Cells; D018411:Spodoptera
chemical_list: D018698:Glutamic Acid; D007608:Kainic Acid; D008024:Ligands; D020033:Protein Isoforms; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins