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

Mads Beich-Frandsen; Darryl S Pickering; Osman Mirza; Tommy N Johansen; Jeremy Greenwood; Bente Vestergaard; Arne Schousboe; Michael Gajhede; Tommy Liljefors; Jette S Kastrup

doi:10.1021/jm701126w

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

Mads Beich-Frandsen, Darryl S Pickering, Osman Mirza, Tommy N Johansen, Jeremy Greenwood, Bente Vestergaard, Arne Schousboe, Michael Gajhede, Tommy Liljefors, Jette S Kastrup

Research output: Contribution to journal › Journal article › Research › peer-review

9 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	5
Pages (from-to)	1459-63
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm701126w
Publication status	Published - 2008

Bibliographical note

Keywords: Alanine; Binding Sites; Crystallography, X-Ray; Ligands; Models, Molecular; Radioligand Assay; Receptors, AMPA; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Thiadiazoles

Keywords

Former Faculty of Pharmaceutical Sciences

Access to Document

10.1021/jm701126w

Cite this

Beich-Frandsen, M., Pickering, D. S., Mirza, O., Johansen, T. N., Greenwood, J., Vestergaard, B., Schousboe, A., Gajhede, M., Liljefors, T., & Kastrup, J. S. (2008). 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. Journal of Medicinal Chemistry, 51(5), 1459-63. https://doi.org/10.1021/jm701126w

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.

In: Journal of Medicinal Chemistry, Vol. 51, No. 5, 2008, p. 1459-63.

Research output: Contribution to journal › Journal article › Research › peer-review

Beich-Frandsen, M, Pickering, DS , Mirza, O , Johansen, TN, Greenwood, J, Vestergaard, B , Schousboe, A , Gajhede, M, Liljefors, T & Kastrup, JS 2008, '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', Journal of Medicinal Chemistry, vol. 51, no. 5, pp. 1459-63. https://doi.org/10.1021/jm701126w

Beich-Frandsen, Mads ; Pickering, Darryl S ; Mirza, Osman ; Johansen, Tommy N ; Greenwood, Jeremy ; Vestergaard, Bente ; Schousboe, Arne ; Gajhede, Michael ; Liljefors, Tommy ; Kastrup, Jette S. / 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. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 5. pp. 1459-63.

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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.",

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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

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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.

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