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Title
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Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2.
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Authors
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A.Frandsen,
D.S.Pickering,
B.Vestergaard,
C.Kasper,
B.B.Nielsen,
J.R.Greenwood,
G.Campiani,
C.Fattorusso,
M.Gajhede,
A.Schousboe,
J.S.Kastrup.
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Ref.
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Mol Pharmacol, 2005,
67,
703-713.
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PubMed id
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Abstract
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Ionotropic glutamate receptors mediate most rapid excitatory synaptic
transmission in the mammalian central nervous system, and their involvement in
neurological diseases has stimulated widespread interest in their structure and
function. Despite a large number of agonists developed so far, few display
selectivity among (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid
(AMPA)-receptor subtypes. The present study provides X-ray structures of the
glutamate receptor 2 (GluR2)-selective partial agonist
(S)-2-amino-3-(1,3,5,6,7-pentahydro-2,4-dioxocyclopenta[e] pyrimidin-1-yl)
propanoic acid [(S)-CPW399] in complex with the ligand-binding core of GluR2
(GluR2-S1S2J) and with a (Y702F)GluR2-S1S2J mutant. In addition, the structure
of the nonselective partial agonist kainate in complex with (Y702F)GluR2-S1S2J
was determined. The results show that the selectivity of (S)-CPW399 toward
full-length GluR2 relative to GluR3 is reflected in the binding data on the two
soluble constructs, allowing the use of (Y702F)GluR2-S1S2J as a model system for
studying GluR2/GluR3 selectivity. Structural comparisons suggest that
selectivity arises from disruption of a water-mediated network between ligand
and receptor. A D1-D2 domain closure occurs upon agonist binding. (S)-CPW399 and
kainate induce greater domain closure in the Y702F mutant, indicating that these
partial agonists here act in a manner more reminiscent of full agonists. Both
kainate and (S)-CPW399 exhibited higher efficacy at (Y702F)GluR2(Q)i than at
wild-type GluR2(Q)i. Whereas an excellent correlation exists between domain
closure and efficacy of a range of agonists at full-length GluR2 determined by
electrophysiology in Xenopus laevis oocytes, a direct correlation between
agonist induced domain closure of (Y702F)GluR2-S1S2J and efficacy at the GluR3
receptor is not observed. Although it clearly controls selectivity, mutation of
this residue alone is insufficient to explain agonist-induced conformational
rearrangements occurring in this variant.
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