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

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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 articleResearchpeer-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., ... 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 = "1",
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