title: Structure of the kainate receptor subunit GluR6 agonist-binding domain complexed with domoic acid.
abstract: We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the kainate receptor subunit GluR6, in complex with the agonist domoate. The structure shows the expected overall homology with AMPA and NMDA receptor subunit structures but reveals an unexpected binding mode for the side chain of domoate, in which contact is made to the larger lobe only (lobe I). In common with the AMPA receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved. Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not. The structure incorporates native glycosylation, which has not previously been described for ionotropic glutamate receptors. The position of the sugars near the subunit interface rules out their direct involvement in subunit association but leaves open the possibility of indirect modulation. Finally, we observed several tetrameric assemblies that satisfy topological constraints with respect to connection to the receptor pore, and which are therefore candidates for the native quaternary structure.
authors.affiliation: Structural Biology Laboratory and Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Max H
authors.initials: MH
authors.lastname: Nanao
authors.forename: Tim
authors.initials: T
authors.lastname: Green
authors.forename: Yael
authors.initials: Y
authors.lastname: Stern-Bach
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Heinemann
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000493:pharmacokinetics; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D000097806:GluK2 Kainate Receptor
chemical_list: D007608:Kainic Acid; D009498:Neurotoxins; D021122:Protein Subunits; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C012301:domoic acid; C104722:glutamate receptor ionotropic, AMPA 2