3tkd

Publication Abstract from PubMed

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 microM (H = -4.9 kcal/mol, -TS = -2.3 kcal/mol). BPAM-97 was used in a displacement assay to determine Kd of 0.46 mM (H = -1.2 kcal/mol, -TS = -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.

Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2.,Krintel C, Frydenvang K, Olsen L, Kristensen MT, de Barrios O, Naur P, Francotte P, Pirotte B, Gajhede M, Kastrup JS Biochem J. 2011 Sep 7. PMID:21895609^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.