The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2
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The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. / Bay, Yasmin; Egeberg Jeppesen, Mie; Frydenvang, Karla; Francotte, Pierre; Pirotte, Bernard; Pickering, Darryl S.; Kristensen, Anders Skov; Kastrup, Jette Sandholm.
In: FEBS Letters, Vol. 598, No. 7, 2024, p. 743-757.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2
AU - Bay, Yasmin
AU - Egeberg Jeppesen, Mie
AU - Frydenvang, Karla
AU - Francotte, Pierre
AU - Pirotte, Bernard
AU - Pickering, Darryl S.
AU - Kristensen, Anders Skov
AU - Kastrup, Jette Sandholm
N1 - Publisher Copyright: © 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - BPAM344 binding mode
KW - calcium-sensitive fluorescence-based assay
KW - dimer interface
KW - GluK2 mutations
KW - positive allosteric modulation
KW - X-ray crystallography
U2 - 10.1002/1873-3468.14824
DO - 10.1002/1873-3468.14824
M3 - Journal article
C2 - 38369668
AN - SCOPUS:85185969795
VL - 598
SP - 743
EP - 757
JO - F E B S Letters
JF - F E B S Letters
SN - 0014-5793
IS - 7
ER -
ID: 387023158