The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | FEBS Letters |
| Vol/bind | 598 |
| Udgave nummer | 7 |
| Sider (fra-til) | 743-757 |
| ISSN | 0014-5793 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
Beamline scientists at the MAX IV Laboratory, Lund, Sweden, are thanked for technical assistance. Linda Grønborg Dorvil is thanked for her technical support in the process of creating mutant constructs. Christophe Mulle is thanked for providing the GluK2() construct. Christina Kasper is thanked for providing the GluK2‐LBD (S1S2) construct and Heidi Peterson for technical assistance in expressing and purifying the GluK2‐LBD protein. The Independent Research Fund Denmark – Medical Sciences (YB, JSK) and Danscatt (YB, MEJ, KF, JSK) are acknowledged for financial support. We acknowledge the MAX IV Laboratory for time on Beamline BioMAX under proposal MX20200259. All funding sources had no part in the design of the study, the collection of data, or the analysis and interpretation, as well as no involvement in writing the manuscript or decision‐making of publication. Q
Publisher Copyright:
© 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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