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

Harvard

Bay, Y, Egeberg Jeppesen, M, Frydenvang, K, Francotte, P, Pirotte, B, Pickering, DS, Kristensen, AS & Kastrup, JS 2024, 'The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2', FEBS Letters, vol. 598, no. 7, pp. 743-757. https://doi.org/10.1002/1873-3468.14824

APA

Bay, Y., Egeberg Jeppesen, M., Frydenvang, K., Francotte, P., Pirotte, B., Pickering, D. S., Kristensen, A. S., & Kastrup, J. S. (2024). The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. FEBS Letters, 598(7), 743-757. https://doi.org/10.1002/1873-3468.14824

Vancouver

Bay Y, Egeberg Jeppesen M, Frydenvang K, Francotte P, Pirotte B, Pickering DS et al. The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. FEBS Letters. 2024;598(7):743-757. https://doi.org/10.1002/1873-3468.14824

Author

Bay, Yasmin ; Egeberg Jeppesen, Mie ; Frydenvang, Karla ; Francotte, Pierre ; Pirotte, Bernard ; Pickering, Darryl S. ; Kristensen, Anders Skov ; Kastrup, Jette Sandholm. / The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2. In: FEBS Letters. 2024 ; Vol. 598, No. 7. pp. 743-757.

Bibtex

@article{edc0b943651d4436ac3782f7e06d37e7,
title = "The positive allosteric modulator BPAM344 and L-glutamate introduce an active-like structure of the ligand-binding domain of GluK2",
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.",
keywords = "BPAM344 binding mode, calcium-sensitive fluorescence-based assay, dimer interface, GluK2 mutations, positive allosteric modulation, X-ray crystallography",
author = "Yasmin Bay and {Egeberg Jeppesen}, Mie and Karla Frydenvang and Pierre Francotte and Bernard Pirotte and Pickering, {Darryl S.} and Kristensen, {Anders Skov} and Kastrup, {Jette Sandholm}",
note = "Publisher Copyright: {\textcopyright} 2024 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.",
year = "2024",
doi = "10.1002/1873-3468.14824",
language = "English",
volume = "598",
pages = "743--757",
journal = "F E B S Letters",
issn = "0014-5793",
publisher = "JohnWiley & Sons Ltd",
number = "7",

}

RIS

TY - JOUR

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