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

8 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

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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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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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

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

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

year = "2008",

doi = "10.1021/jm701126w",

language = "English",

volume = "51",

pages = "1459--63",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

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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

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

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SN - 0022-2623

VL - 51

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EP - 1463

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

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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