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

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

9 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	51
Udgave nummer	5
Sider (fra-til)	1459-63
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm701126w
Status	Udgivet - 2008

Bibliografisk note

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

Emneord

Det tidligere Farmaceutiske Fakultet

Adgang til dokumentet

10.1021/jm701126w

Citationsformater

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 et al.
I: Journal of Medicinal Chemistry, Bind 51, Nr. 5, 2008, s. 1459-63.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 51, nr. 5, s. 1459-63. https://doi.org/10.1021/jm701126w

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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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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

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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.

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