Abstract
Kainate 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 crystal structure of the dimeric 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 in modulating 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 in the design of compounds targeting kainate receptors, expanding their potential as targets for the treatment of brain diseases.
Original language | English |
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Journal | FEBS Letters |
Volume | 598 |
Issue number | 7 |
Pages (from-to) | 743-757 |
ISSN | 0014-5793 |
DOIs | |
Publication status | Published - 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Keywords
- BPAM344 binding mode
- calcium-sensitive fluorescence-based assay
- dimer interface
- GluK2 mutations
- positive allosteric modulation
- X-ray crystallography