Reference : Thermodynamics and structural analysis of positive allosteric modulation of the iono...
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 mailto [Université de Liège - ULg > Département de pharmacie > Chimie pharmaceutique >]
Pirotte, Bernard mailto [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
Yes (verified by ORBi)
International
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
Researchers
http://hdl.handle.net/2268/125466
10.1042/BJ20111221

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