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Glutamate receptor (GluR) ion channels mediate fast synaptic transmission in the
mammalian CNS. Numerous crystallographic studies, the majority on the
GluR2-subtype AMPA receptor, have revealed the structural basis for binding of
subtype-specific agonists. In contrast, because there are far fewer
antagonist-bound structures, the mechanisms for antagonist binding are much less
well understood, particularly for kainate receptors that exist as multiple
subtypes with a distinct biology encoded by the GluR5-7, KA1, and KA2 genes. We
describe here high-resolution crystal structures for the GluR5 ligand-binding
core complex with UBP302 and UBP310, novel GluR5-selective antagonists. The
crystal structures reveal the structural basis for the high selectivity for
GluR5 observed in radiolabel displacement assays for the isolated ligand binding
cores of the GluR2, GluR5, and GluR6 subunits and during inhibition of
glutamate-activated currents in studies on full-length ion channels. The
antagonists bind via a novel mechanism and do not form direct contacts with the
E723 side chain as occurs in all previously solved AMPA and kainate receptor
agonist and antagonist complexes. This results from a hyperextension of the
ligand binding core compared with previously solved structures. As a result, in
dimer assemblies, there is a 22 A extension of the ion channel linkers in the
transition from antagonist- to glutamate-bound forms. This large conformational
change is substantially different from that described for AMPA receptors, was
not possible to predict from previous work, and suggests that glutamate
receptors are capable of much larger movements than previously thought.
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