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| Référence : Thermodynamics and structural analysis of positive allosteric modulation of the ionotro... |
| Scientific journals : Article | |||
| Life sciences : Biochemistry, biophysics & molecular biology Human health sciences : Pharmacy, pharmacology & toxicology Physical, chemical, mathematical & earth Sciences : Chemistry | |||
| http://hdl.handle.net/2268/125466 | |||
| Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2 | |
| English | |
| Krintel, Christian [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| Frydenvang, Karla [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| Olsen, Lars [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| Kristensen, Maria [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| de Barrios, Oriol [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| Naur, Peter [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
Francotte, Pierre  [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >] | |
| Pirotte, Bernard [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >] | |
| Gajhede, Michael [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| Kastrup, Jette [University of Copenhagen > Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, > > >] | |
| 2012 | |
| Biochemical Journal | |
| Portland Press | |
| 441 | |
| 173-178 | |
| Internationale | |
| 0264-6021 | |
| 1470-8728 | |
| London | |
| United Kingdom | |
| [en] binding affinity ; crystal structure ; ionotropic glutamate receptor ; isothermal titration calorimetry ; positive allosteric modulator | |
| [en] 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 LBD (ligand-binding domain) and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. In the present study, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the LBD of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was used. The potent GluA2 modulator BPAM-97 was used as a 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 aKd of 5.6 μM (Δ H = − 4.9 kcal/mol, − T Δ S = − 2.3 kcal/mol; where 1 kcal ≈4.187 kJ). BPAM-97 was used in a displacement assay to determine a Kd of 0.46 mM (Δ H = − 1.2 kcal/mol, − T Δ S = − 3.3 kcal/mol) for the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased van der Waals contacts to, primarily, Met496 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 the development of drugs against cognitive disorders. Key words: binding affinity, crystal structure, ionotropic glutamate receptor, isothermal titration calorimetry, positive allosteric modulator | |
| Chercheurs | |
| http://hdl.handle.net/2268/125466 | |
| 10.1042/BJ20111221 |
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