Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Competitive antagonism of AMPA receptors by ligands of different classes : crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. / Hogner, Anders; Greenwood, Jeremy R; Liljefors, Tommy; Lunn, Marie-Louise; Egebjerg, Jan; Larsen, Ingrid K; Gouaux, Eric; Kastrup, Jette Sandholm Jensen.

In: Journal of Medicinal Chemistry, Vol. 46, No. 2, 16.01.2003, p. 214-21.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Hogner, A, Greenwood, JR, Liljefors, T, Lunn, M-L, Egebjerg, J, Larsen, IK, Gouaux, E & Kastrup, JSJ 2003, 'Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX', Journal of Medicinal Chemistry, vol. 46, no. 2, pp. 214-21. https://doi.org/10.1021/jm020989v

APA

Hogner, A., Greenwood, J. R., Liljefors, T., Lunn, M-L., Egebjerg, J., Larsen, I. K., ... Kastrup, J. S. J. (2003). Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. Journal of Medicinal Chemistry, 46(2), 214-21. https://doi.org/10.1021/jm020989v

Vancouver

Hogner A, Greenwood JR, Liljefors T, Lunn M-L, Egebjerg J, Larsen IK et al. Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. Journal of Medicinal Chemistry. 2003 Jan 16;46(2):214-21. https://doi.org/10.1021/jm020989v

Author

Hogner, Anders ; Greenwood, Jeremy R ; Liljefors, Tommy ; Lunn, Marie-Louise ; Egebjerg, Jan ; Larsen, Ingrid K ; Gouaux, Eric ; Kastrup, Jette Sandholm Jensen. / Competitive antagonism of AMPA receptors by ligands of different classes : crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 2. pp. 214-21.

Bibtex

@article{d493f1f622e741ab9f140b1682317f17,
title = "Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX",
abstract = "Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.",
keywords = "Binding Sites, Crystallography, X-Ray, Excitatory Amino Acid Antagonists, Isoxazoles, Ligands, Models, Molecular, Organophosphonates, Quinoxalines, Receptors, AMPA",
author = "Anders Hogner and Greenwood, {Jeremy R} and Tommy Liljefors and Marie-Louise Lunn and Jan Egebjerg and Larsen, {Ingrid K} and Eric Gouaux and Kastrup, {Jette Sandholm Jensen}",
year = "2003",
month = "1",
day = "16",
doi = "10.1021/jm020989v",
language = "English",
volume = "46",
pages = "214--21",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

RIS

TY - JOUR

T1 - Competitive antagonism of AMPA receptors by ligands of different classes

T2 - crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX

AU - Hogner, Anders

AU - Greenwood, Jeremy R

AU - Liljefors, Tommy

AU - Lunn, Marie-Louise

AU - Egebjerg, Jan

AU - Larsen, Ingrid K

AU - Gouaux, Eric

AU - Kastrup, Jette Sandholm Jensen

PY - 2003/1/16

Y1 - 2003/1/16

N2 - Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.

AB - Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels that are essential for mediating fast synaptic transmission in the central nervous system. This study presents a high-resolution X-ray structure of the competitive antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals that ATPO and DNQX stabilize an open form of the ligand-binding core by different sets of interactions. Computational techniques are used to quantify the differences between these two ligands and to map the binding site. The isoxazole moiety of ATPO acts primarily as a spacer, and other scaffolds could potentially be used. Whereas agonists induce substantial domain closures compared to the apo structure, ATPO only induces minor conformational changes. These results are consistent with the hypothesis that domain closure is related to receptor activation. To facilitate the design of novel AMPA receptor antagonists, we present a modified model of the binding site that includes key residues involved in ligand recognition.

KW - Binding Sites

KW - Crystallography, X-Ray

KW - Excitatory Amino Acid Antagonists

KW - Isoxazoles

KW - Ligands

KW - Models, Molecular

KW - Organophosphonates

KW - Quinoxalines

KW - Receptors, AMPA

U2 - 10.1021/jm020989v

DO - 10.1021/jm020989v

M3 - Journal article

C2 - 12519060

VL - 46

SP - 214

EP - 221

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -

ID: 44729610