Structural analysis and thermodynamics of the ionotropic glutamate receptor GluA2 modulator BPAM-97

Ionotropic glutamate receptors are tetrameric ligand gated ion channels that mediate in ux and ef ux of metal ions in response to glutamate. Positive allosteric modulators of the ionotropic glutamate receptor 2 (GluA2) are promising lead compounds for drugs against cognitive disorders. These compounds bind within the dimeric interface formed by the receptor ligand binding domains (LBDs) attenuating deactivation and desensitisation. In this study we determined the structure of the complex formed between a dimeric GluA2 LBD-L483Y-N754S mutant and the potent novel modulator BPAM-97 by X-ray crystallography. We provide a molecular explanation for the 200 fold increased potency of BPAM-97 compared to its parent compound IDRA-21. We also utilized isothermal titration calorimetry to measure the binding af nity and thermodynamics of the LBD-L483Y-N754S:BPAM-97 complex formation as well as that for the non-dimeric LBD-N754S:BPAM-97. (Less)