Structural basis of T-loop-independent recognition and activation of CDKs by the CDK-activating kinase

• 成果类型: Article
• 署名作者: Cushing, Victoria I.; McGeoch, Amy J. S.; Williams, Sophie L.; Roumeliotis, Theodoros I.; Feng, Junjie; Dan, Lucy M.; Choudhary, Jyoti S.; Davey, Norman E.; Greber, Basil J.
• 署名单位: University of London; Royal Marsden NHS Foundation Trust; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; University of London; Royal Marsden NHS Foundation Trust; Institute of Cancer Research - UK; Royal Marsden NHS Foundation Trust; University of London; Institute of Cancer Research - UK; Imperial College London; Francis Crick Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adw0053
• 发表日期: 2025-11-27
• 页码: 911-917
• 关键词: CYCLIN-DEPENDENT KINASES; cryo-em; crystal-structure; protein-kinase; transition-state; phosphorylation; inhibitor; complex; specificity; orientation

摘要

Cyclin-dependent kinases (CDKs) are prototypical regulators of the cell cycle. The CDK-activating kinase (CAK) acts as a master regulator of CDK activity by catalyzing the activating phosphorylation of CDKs on a conserved threonine residue within the regulatory T-loop. However, structural data illuminating the mechanism by which the CAK recognizes and activates CDKs have remained elusive. In this study, we determined high-resolution structures of the CAK in complex with CDK2 and CDK2-cyclin A2 by cryogenic electron microscopy. Our structures reveal a T-loop-independent kinase-kinase interface with contributions from both kinase lobes. Computational analysis and structures of the CAK in complex with CDK1-cyclin B1 and CDK11 indicate that these structures represent the general architecture of CAK-CDK complexes. These results advance our mechanistic understanding of cell cycle regulation and kinase signaling cascades.