Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain

Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain. Their dysfunction is implicated in many neurological disorders, rendering iGluRs potential drug targets. Here, we performed a systematic analysis of the druggability of two major iGluR subfamilies, using molecular dynamics simulations in the presence of drug-like molecules. We demonstrate the applicability of druggability simulations by faithfully identifying known agonist and modulator sites on AMPA receptors (AMPARs) and NMDA receptors. Simulations produced the expected allosteric changes of the AMPAR ligand-binding domain in response to agonist. We also identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), resulting from its unique conformational flexibility that we explored further with crystal structures trapped in vastly different states. In addition to providing an in-depth analysis into iGluR NTD dynamics, our approach identifies druggable sites and permits the determination of pharmacophoric features toward novel iGluR modulators. [Display omitted] •Known agonist and modulator sites were confirmed on AMPA and NMDA receptors•A ligand-binding site was identified in the AMPAR GluA3 NTD•Ligand binding is dependent on conformational flexibility•Additional crystal structures support the role of GluA3 NTD conformation plasticity Lee et al. assess the druggability of the ionotropic glutamate receptor subfamilies, using molecular dynamics simulations in the presence of drug-like molecules and X-ray crystallography. The study presents a ligand-binding site in the GluA3 N-terminal domain and supports the role of conformational plasticity in modulating ligand binding.