Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain.

ABSTRACT: Ionotropic glutamate receptors mediate the majority of vertebrate excitatory synaptic transmission. The development of selective antagonists for glutamate receptor subtypes is of interest in the treatment of a variety of neurological disorders. This study presents the crystal structure of the binding domain of GluR2 bound to two antagonists (UBP277 and UBP282) that are derivatives of the natural product, willardiine. The antagonists bind to one lobe of the protein with interactions similar to agonists. Interaction with the second lobe differs between the two antagonists, resulting in a different position of the uracil ring and different orientations of the bilobed structure. UBP277 binding produces a stable lobe orientation that is similar to the apo state, but the binding of UBP282 produc

SUBMITTER: Ahmed AH 

PROVIDER: S-EPMC2693247 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature