Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

Research output: Contribution to journalJournal articlepeer-review

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Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. / Krintel, Christian; Frydenvang, Karla; Olsen, Lars; Kristensen, Maria T; de Barrios, Oriol; Naur, Peter; Francotte, Pierre; Pirotte, Bernard; Gajhede, Michael; Kastrup, Jette Sandholm.

In: Biochemical Journal, Vol. 441, No. 1, 01.01.2012, p. 173-178.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Krintel, C, Frydenvang, K, Olsen, L, Kristensen, MT, de Barrios, O, Naur, P, Francotte, P, Pirotte, B, Gajhede, M & Kastrup, JS 2012, 'Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2', Biochemical Journal, vol. 441, no. 1, pp. 173-178. https://doi.org/10.1042/BJ20111221

APA

Krintel, C., Frydenvang, K., Olsen, L., Kristensen, M. T., de Barrios, O., Naur, P., Francotte, P., Pirotte, B., Gajhede, M., & Kastrup, J. S. (2012). Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. Biochemical Journal, 441(1), 173-178. https://doi.org/10.1042/BJ20111221

Vancouver

Krintel C, Frydenvang K, Olsen L, Kristensen MT, de Barrios O, Naur P et al. Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. Biochemical Journal. 2012 Jan 1;441(1):173-178. https://doi.org/10.1042/BJ20111221

Author

Krintel, Christian ; Frydenvang, Karla ; Olsen, Lars ; Kristensen, Maria T ; de Barrios, Oriol ; Naur, Peter ; Francotte, Pierre ; Pirotte, Bernard ; Gajhede, Michael ; Kastrup, Jette Sandholm. / Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. In: Biochemical Journal. 2012 ; Vol. 441, No. 1. pp. 173-178.

Bibtex

@article{96a123a31c69469ea90873c318655596,
title = "Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2",
abstract = "Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the ligand-binding domain and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. Here, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the ligand-binding domain of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was utilized. The potent GluA2 modulator BPAM-97 was used as reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has Kd of 5.6 µM (¿H = -4.9 kcal/mol, -T¿S = -2.3 kcal/mol). BPAM-97 was used in a displacement assay to determine Kd of 0.46 mM (¿H = -1.2 kcal/mol, -T¿S = -3.3 kcal/mol) of the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased vdW contacts to primarily Met-496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in development of drugs against cognitive disorders.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Christian Krintel and Karla Frydenvang and Lars Olsen and Kristensen, {Maria T} and {de Barrios}, Oriol and Peter Naur and Pierre Francotte and Bernard Pirotte and Michael Gajhede and Kastrup, {Jette Sandholm}",
note = "Keywords: ionotropic glutamate receptors, positive allosteric modulators, isothermal titration calorimetry, crystal structure, binding affinity",
year = "2012",
month = jan,
day = "1",
doi = "10.1042/BJ20111221",
language = "English",
volume = "441",
pages = "173--178",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2

AU - Krintel, Christian

AU - Frydenvang, Karla

AU - Olsen, Lars

AU - Kristensen, Maria T

AU - de Barrios, Oriol

AU - Naur, Peter

AU - Francotte, Pierre

AU - Pirotte, Bernard

AU - Gajhede, Michael

AU - Kastrup, Jette Sandholm

N1 - Keywords: ionotropic glutamate receptors, positive allosteric modulators, isothermal titration calorimetry, crystal structure, binding affinity

PY - 2012/1/1

Y1 - 2012/1/1

N2 - Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the ligand-binding domain and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. Here, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the ligand-binding domain of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was utilized. The potent GluA2 modulator BPAM-97 was used as reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has Kd of 5.6 µM (¿H = -4.9 kcal/mol, -T¿S = -2.3 kcal/mol). BPAM-97 was used in a displacement assay to determine Kd of 0.46 mM (¿H = -1.2 kcal/mol, -T¿S = -3.3 kcal/mol) of the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased vdW contacts to primarily Met-496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in development of drugs against cognitive disorders.

AB - Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the ligand-binding domain and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. Here, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the ligand-binding domain of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was utilized. The potent GluA2 modulator BPAM-97 was used as reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has Kd of 5.6 µM (¿H = -4.9 kcal/mol, -T¿S = -2.3 kcal/mol). BPAM-97 was used in a displacement assay to determine Kd of 0.46 mM (¿H = -1.2 kcal/mol, -T¿S = -3.3 kcal/mol) of the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased vdW contacts to primarily Met-496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in development of drugs against cognitive disorders.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1042/BJ20111221

DO - 10.1042/BJ20111221

M3 - Journal article

C2 - 21895609

VL - 441

SP - 173

EP - 178

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 1

ER -

ID: 34367034