title: Structures of the ligand-binding core of iGluR2 in complex with the agonists (R)- and (S)-2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)propionic acid explain their unusual equipotency.
abstract: AMPA-type ionotropic glutamate receptors generally display high stereoselectivity in agonist binding. However, the stereoisomers of 2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)propionic acid (TDPA) have similar enantiopharmacology. To understand this observation, we have determined the X-ray structures of ( R)-TDPA and ( S)-TDPA in complex with the ligand-binding core of iGluR2 and investigated the binding pharmacology at AMPA and kainate receptors. Both enantiomers induce full domain closure in iGluR2 but adopt different conformations when binding to the receptor, which may explain the similar enantiopharmacology.
authors.affiliation: Department of Medicinal Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Beich-Frandsen
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Osman
authors.initials: O
authors.lastname: Mirza
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
authors.forename: Jeremy
authors.initials: J
authors.lastname: Greenwood
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Michael
authors.initials: M
authors.lastname: Gajhede
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D018091:Receptors, AMPA / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: C529299:2-amino-3-(4-hydroxy-1,2,5-thiadiazol-3-yl)propionic acid; D008024:Ligands; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D013830:Thiadiazoles; D000409:Alanine; C104722:glutamate receptor ionotropic, AMPA 2