Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a hallmark regulator of synaptic plasticity, learning, and long-term memory potentiation (LTP). CaMKII is encoded by four highly conserved paralogs in vertebrates (α, β, γ, and δ), each comprising a kinase domain, regulatory segment, variable linker region, and an oligomerizing hub domain that assembles individual CaMKII subunits into a dodecameric or tetradecameric holoenzyme complex. Recent studies have identified a specific high-affinity binding site for γ-hydroxybutyrate (GHB) and related analogs within the hub domain of human CaMKIIα, where ligand binding stabilizes the hub and confers neuroprotection. Studies have indicated that low-dose GHB demonstrated sustained neuroprotection in a mouse model of cerebral ischemia when neurons were exposed to excitotoxicity, as well as thermal stability of the hub, which could alter holoenzyme functionality. The molecular mechanisms of neuroprotection are unknown, and the goal of this study is to elucidate them through X-ray crystallography. Herein, we show experiments to obtain a high-resolution X-ray crystal structure of the CaMKIIα hub domain bound to the GHB analogs KD-35 and KD-37. The crystal structure will reveal the molecular details of the deep binding site that mediates highly specific ligand recognition. These molecular insights define the structural basis for CaMKII–GHB analog interactions and establish a potential framework for pharmacological targeting of CaMKIIα.