Active-like structure of the ligand-binding domain of GluK2 with L-glutamate and the positive allosteric modulator BPAM344

Abstract

AbstractKainate receptors belong to the family of ionotropic glutamate receptors and contribute to the majority of fast excitatory neurotransmission. Consequently, they also play a role in brain diseases. Therefore, understanding how these receptors can be modulated is of importance. Our study provides a dimeric crystal structure of the ligand-binding domain of the kainate receptor GluK2 in complex with L-glutamate and the small molecule positive allosteric modulator, BPAM344, in an active-like conformation. The role of Thr535 and Gln786 for modulation of GluK2 by BPAM344 was investigated using a calcium-sensitive fluorescence-based assay on transiently transfected cells expressing GluK2 and mutants hereof. This study may aid design of tool compounds targeting kainate receptors, elucidating their potential as targets for treatment of brain diseases.