The α-kinase eukaryotic elongation factor 2 kinase (eEF-2K) regulates translational elongation by phosphorylating its ribosome-associated substrate, the GTPase eEF-2. eEF-2K is activated by calmodulin (CaM) through a distinctive mechanism unlike that in other CaM-dependent kinases (CAMK). We describe recent structural insights into this unique activation process and examine the effects of specific regulatory signals on this mechanism. We also highlight key unanswered questions to guide future structure–function studies. These include structural mechanisms which enable eEF-2K to interact with upstream/downstream partners and facilitate its integration of diverse inputs, including Ca²⁺ transients, phosphorylation mediated by energy/nutrient-sensing pathways, pH changes, and metabolites. Answering these questions is key to establishing how eEF-2K harmonizes translation with cellular requirements within the boundaries of its molecular landscape.

α-激酶真核延伸因子 2 激酶 (eEF-2K) 通过磷酸化其核糖体相关底物 GTPase eEF-2 来调节翻译延伸。 eEF-2K 通过与其他 CaM 依赖性激酶 (CAMK) 不同的独特机制被钙调蛋白 (CaM) 激活。我们描述了对这种独特激活过程的最新结构见解，并检查了特定调节信号对该机制的影响。我们还强调了未解答的关键问题，以指导未来的结构功能研究。其中包括使 eEF-2K 能够与上游/下游伙伴相互作用并促进其整合不同输入的结构机制，包括 Ca ²⁺瞬变、能量/营养感应途径介导的磷酸化、pH 变化和代谢物。回答这些问题是确定 eEF-2K 如何在其分子景观范围内协调翻译与细胞需求的关键。