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
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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. / Beich-Frandsen, Mads; Pickering, Darryl S; Mirza, Osman; Johansen, Tommy N; Greenwood, Jeremy; Vestergaard, Bente; Schousboe, Arne; Gajhede, Michael; Liljefors, Tommy; Kastrup, Jette S.
I: Journal of Medicinal Chemistry, Bind 51, Nr. 5, 2008, s. 1459-63.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - 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
AU - Beich-Frandsen, Mads
AU - Pickering, Darryl S
AU - Mirza, Osman
AU - Johansen, Tommy N
AU - Greenwood, Jeremy
AU - Vestergaard, Bente
AU - Schousboe, Arne
AU - Gajhede, Michael
AU - Liljefors, Tommy
AU - Kastrup, Jette S
N1 - Keywords: Alanine; Binding Sites; Crystallography, X-Ray; Ligands; Models, Molecular; Radioligand Assay; Receptors, AMPA; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Thiadiazoles
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm701126w
DO - 10.1021/jm701126w
M3 - Journal article
C2 - 18269227
VL - 51
SP - 1459
EP - 1463
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -
ID: 6747651