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
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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 journal › Journal article › Research › peer-review
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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