The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. / Kasper, Christina; Pickering, Darryl S; Mirza, Osman; Olsen, Lars; Kristensen, Anders S; Greenwood, Jeremy R; Liljefors, Tommy; Schousboe, Arne; Wätjen, Frank; Gajhede, Michael; Sigurskjold, Bent W; Kastrup, Jette S.

In: Journal of Molecular Biology, Vol. 357, No. 4, 2006, p. 1184-201.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Kasper, C, Pickering, DS, Mirza, O, Olsen, L, Kristensen, AS, Greenwood, JR, Liljefors, T, Schousboe, A, Wätjen, F, Gajhede, M, Sigurskjold, BW & Kastrup, JS 2006, 'The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209', Journal of Molecular Biology, vol. 357, no. 4, pp. 1184-201. https://doi.org/10.1016/j.jmb.2006.01.024

APA

Kasper, C., Pickering, D. S., Mirza, O., Olsen, L., Kristensen, A. S., Greenwood, J. R., ... Kastrup, J. S. (2006). The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. Journal of Molecular Biology, 357(4), 1184-201. https://doi.org/10.1016/j.jmb.2006.01.024

Vancouver

Kasper C, Pickering DS, Mirza O, Olsen L, Kristensen AS, Greenwood JR et al. The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. Journal of Molecular Biology. 2006;357(4):1184-201. https://doi.org/10.1016/j.jmb.2006.01.024

Author

Kasper, Christina ; Pickering, Darryl S ; Mirza, Osman ; Olsen, Lars ; Kristensen, Anders S ; Greenwood, Jeremy R ; Liljefors, Tommy ; Schousboe, Arne ; Wätjen, Frank ; Gajhede, Michael ; Sigurskjold, Bent W ; Kastrup, Jette S. / The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209. In: Journal of Molecular Biology. 2006 ; Vol. 357, No. 4. pp. 1184-201.

Bibtex

@article{5497cf806e9211df928f000ea68e967b,
title = "The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209",
abstract = "Ionotropic glutamate receptors (iGluRs) mediate fast synaptic transmission between cells of the central nervous system and are involved in various aspects of normal brain function. iGluRs are implicated in several brain disorders, e.g. in the high-frequency discharge of impulses during an epileptic seizure. (RS)-NS1209 functions as a competitive antagonist at 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptors, and shows robust preclinical anticonvulsant and neuroprotective effects. This study explores 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptor binding and selectivity of this novel class of antagonists. We present here the first X-ray structure of a mixed GluR2 ligand-binding core dimer, with the high-affinity antagonist (S)-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime [(S)-NS1209] in one protomer and the endogenous ligand (S)-glutamate in the other. (S)-NS1209 stabilises an even more open conformation of the D1 and D2 domains of the ligand-binding core than that of the apo structure due to steric hindrance. This is the first time ligand-induced hyperextension of the binding domains has been observed. (S)-NS1209 adopts a novel binding mode, including hydrogen bonding to Tyr450 and Gly451 of D1. Parts of (S)-NS1209 occupy new areas of the GluR2 ligand-binding cleft, and bind near residues that are not conserved among receptor subtypes. The affinities of (RS)-NS1209 at the GluR2 ligand-binding core as well as at GluR1-6 and mutated GluR1 and GluR3 receptors have been measured. Two distinct binding affinities were observed at the GluR3 and GluR4 receptors. In a functional in vitro assay, no difference in potency was observed between GluR2(Q)(o) and GluR3(o) receptors. The thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO to the GluR2 ligand-binding core have been determined by displacement isothermal titration calorimetry. The displacement of (S)-glutamate by all antagonists was shown to be driven by enthalpy.",
author = "Christina Kasper and Pickering, {Darryl S} and Osman Mirza and Lars Olsen and Kristensen, {Anders S} and Greenwood, {Jeremy R} and Tommy Liljefors and Arne Schousboe and Frank W{\"a}tjen and Michael Gajhede and Sigurskjold, {Bent W} and Kastrup, {Jette S}",
note = "Keywords: Animals; Binding Sites; Crystallography, X-Ray; Dimerization; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Hydrogen Bonding; Macromolecular Substances; Models, Molecular; Molecular Structure; Protein Structure, Quaternary; Pyrroles; Quinoxalines; Rats; Receptors, AMPA; Recombinant Proteins; Tetrahydroisoquinolines; Thermodynamics",
year = "2006",
doi = "10.1016/j.jmb.2006.01.024",
language = "English",
volume = "357",
pages = "1184--201",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press",
number = "4",

}

RIS

TY - JOUR

T1 - The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209

AU - Kasper, Christina

AU - Pickering, Darryl S

AU - Mirza, Osman

AU - Olsen, Lars

AU - Kristensen, Anders S

AU - Greenwood, Jeremy R

AU - Liljefors, Tommy

AU - Schousboe, Arne

AU - Wätjen, Frank

AU - Gajhede, Michael

AU - Sigurskjold, Bent W

AU - Kastrup, Jette S

N1 - Keywords: Animals; Binding Sites; Crystallography, X-Ray; Dimerization; Excitatory Amino Acid Antagonists; Glutamic Acid; Humans; Hydrogen Bonding; Macromolecular Substances; Models, Molecular; Molecular Structure; Protein Structure, Quaternary; Pyrroles; Quinoxalines; Rats; Receptors, AMPA; Recombinant Proteins; Tetrahydroisoquinolines; Thermodynamics

PY - 2006

Y1 - 2006

N2 - Ionotropic glutamate receptors (iGluRs) mediate fast synaptic transmission between cells of the central nervous system and are involved in various aspects of normal brain function. iGluRs are implicated in several brain disorders, e.g. in the high-frequency discharge of impulses during an epileptic seizure. (RS)-NS1209 functions as a competitive antagonist at 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptors, and shows robust preclinical anticonvulsant and neuroprotective effects. This study explores 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptor binding and selectivity of this novel class of antagonists. We present here the first X-ray structure of a mixed GluR2 ligand-binding core dimer, with the high-affinity antagonist (S)-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime [(S)-NS1209] in one protomer and the endogenous ligand (S)-glutamate in the other. (S)-NS1209 stabilises an even more open conformation of the D1 and D2 domains of the ligand-binding core than that of the apo structure due to steric hindrance. This is the first time ligand-induced hyperextension of the binding domains has been observed. (S)-NS1209 adopts a novel binding mode, including hydrogen bonding to Tyr450 and Gly451 of D1. Parts of (S)-NS1209 occupy new areas of the GluR2 ligand-binding cleft, and bind near residues that are not conserved among receptor subtypes. The affinities of (RS)-NS1209 at the GluR2 ligand-binding core as well as at GluR1-6 and mutated GluR1 and GluR3 receptors have been measured. Two distinct binding affinities were observed at the GluR3 and GluR4 receptors. In a functional in vitro assay, no difference in potency was observed between GluR2(Q)(o) and GluR3(o) receptors. The thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO to the GluR2 ligand-binding core have been determined by displacement isothermal titration calorimetry. The displacement of (S)-glutamate by all antagonists was shown to be driven by enthalpy.

AB - Ionotropic glutamate receptors (iGluRs) mediate fast synaptic transmission between cells of the central nervous system and are involved in various aspects of normal brain function. iGluRs are implicated in several brain disorders, e.g. in the high-frequency discharge of impulses during an epileptic seizure. (RS)-NS1209 functions as a competitive antagonist at 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptors, and shows robust preclinical anticonvulsant and neuroprotective effects. This study explores 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptor binding and selectivity of this novel class of antagonists. We present here the first X-ray structure of a mixed GluR2 ligand-binding core dimer, with the high-affinity antagonist (S)-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-pyrrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime [(S)-NS1209] in one protomer and the endogenous ligand (S)-glutamate in the other. (S)-NS1209 stabilises an even more open conformation of the D1 and D2 domains of the ligand-binding core than that of the apo structure due to steric hindrance. This is the first time ligand-induced hyperextension of the binding domains has been observed. (S)-NS1209 adopts a novel binding mode, including hydrogen bonding to Tyr450 and Gly451 of D1. Parts of (S)-NS1209 occupy new areas of the GluR2 ligand-binding cleft, and bind near residues that are not conserved among receptor subtypes. The affinities of (RS)-NS1209 at the GluR2 ligand-binding core as well as at GluR1-6 and mutated GluR1 and GluR3 receptors have been measured. Two distinct binding affinities were observed at the GluR3 and GluR4 receptors. In a functional in vitro assay, no difference in potency was observed between GluR2(Q)(o) and GluR3(o) receptors. The thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO to the GluR2 ligand-binding core have been determined by displacement isothermal titration calorimetry. The displacement of (S)-glutamate by all antagonists was shown to be driven by enthalpy.

U2 - 10.1016/j.jmb.2006.01.024

DO - 10.1016/j.jmb.2006.01.024

M3 - Journal article

C2 - 16483599

VL - 357

SP - 1184

EP - 1201

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 4

ER -

ID: 20122981