The human CDK-activating kinase (CAK) is a multifunctional protein complex and key regulator of cell growth and division. Because of its critical functions in regulating the cell cycle and transcription initiation, it is a key target for multiple cancer drug discovery programs. However, the structure of the active human CAK, insights into its regulation, and its interactions with cellular substrates and inhibitors remained elusive until recently due to the lack of high-resolution structures of the intact complex. This review covers the progress in structure determination of the human CAK by cryogenic electron microscopy (cryo-EM), from early efforts to recent near-atomic resolution maps routinely resolved at 2Å or better. These results were enabled by the latest cryo-EM technologies introduced after the initial phase of the “resolution revolution” and allowed the application of high-resolution methods to new classes of molecular targets, including small protein complexes that were intractable using earlier technology.

中文翻译：

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小蛋白质复合物的高分辨率冷冻电镜：人类 CDK 激活激酶的结构

人类 CDK 激活激酶 (CAK) 是一种多功能蛋白质复合物，是细胞生长和分裂的关键调节因子。由于其在调节细胞周期和转录起始方面的关键功能，它是多种癌症药物发现计划的关键目标。然而，由于缺乏完整复合物的高分辨率结构，直到最近，活性人类 CAK 的结构、对其调节的深入了解以及其与细胞底物和抑制剂的相互作用仍然难以捉摸。这篇综述涵盖了通过低温电子显微镜 (cryo-EM) 确定人类 CAK 结构的进展，从早期的努力到最近通常分辨率为 2Å 或更好的近原子分辨率图。这些结果是通过“分辨率革命”初始阶段推出的最新冷冻电镜技术实现的，并允许将高分辨率方法应用于新型分子靶标，包括使用早期技术难以处理的小蛋白质复合物。