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Title
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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.
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Authors
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A.Hogner,
J.R.Greenwood,
T.Liljefors,
M.L.Lunn,
J.Egebjerg,
I.K.Larsen,
E.Gouaux,
J.S.Kastrup.
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Ref.
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J Med Chem, 2003,
46,
214-221.
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PubMed id
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Abstract
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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.
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