Structure-based functional design of chemical ligands for AMPA-subtype glutamate receptors.

摘要

Ionotropic glutamate receptors (GluRs) function as an excitatory transmitter system in the human brain, particularly in learning and memory. Development of small molecules that are capable of selectively potentiating the ion channel activity of AMPA-subtype GluRs holds promise for potential new treatment of neurodegenerative diseases such as Alzheimer's. In working towards this goal, we obtained main-chain nuclear magnetic resonance (NMR) assignments of the extracellular ligand-binding domain of GluR2 that enables us to investigate receptor-ligand interactions in physiological conditions at atomic detail. With NMR structure-based methods, chemical compounds that can selectively modulate the ion chancel activity of GluR2 alone or synergistically with glutamate or kainate were identified. Our NMR structural analysis of GluR2 S1S2 further reveals that the regions of the receptor dimer interface exhibit distinct conformational dynamics, which we hypothesize to be linked to receptor functions in interactions with an agonist or antagonist. This coupling of ligand binding to receptor dimerization, gating, and desensitization may serve as an in vitro biophysical parameter to evaluate potential biological effects of the chemical ligands being developed here.