文章：

PLK1活性的结构调控：对细胞周期功能及药物发现的影响

Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery

原文发布日期：2025-05-16 

英文摘要：

Polo Like Kinase 1 (PLK1), a key regulator of mitosis whose overexpression is often associated with poor survival rates in cancer, continues to be widely investigated as an oncology drug target with clinical trials evaluating second and third generation inhibitors. In addition to the conserved N-terminal kinase domain (KD), a unique characteristic of the Polo-Like kinase family is the C-terminal polo-box domain (PBD). The PBD contains a phosphopeptide binding site that recognizes substrates primed by other kinases and furthermore is responsible for subcellular localization of PLK1 to specific sites in the nucleus including centrosomes and kinetochores. Another role of the PBD is its regulatory ability through domain-domain interactions with the KD to maintain an autoinhibited state of PLK1. Insights into post translational modifications and the PBD – KD domain-domain association have been obtained and show that key events in PLK1 regulation include phosphosubstrate binding, T210 phosphorylation and engagement with the Bora protein. These can induce an open and active conformation where the domain-domain inhibitory interactions no longer dominate. Further regulatory events recently described include the interchange between monomeric and dimeric forms, which can also serve to inhibit or activate PLK1 during the cell cycle. Different oligomeric forms of PLK1, existing as homodimers and heterodimers with PLK2, have been identified and likely play context dependent roles. This review provides an overview of recent information describing structural and mechanistic insights into inhibition of PLK1 and the temporal and spatial requirements of its activation and regulation. It also covers recent insights into the conformational regulation of other members of the Polo-Like kinase family. The implications of the conformational regulation of PLK1 with respect to cell cycle function and drug discovery are significant and are therefore discussed in detail. 

摘要翻译：

Polo样激酶1（PLK1）作为有丝分裂的关键调控因子，其过度表达常与癌症患者不良生存率相关，目前作为肿瘤药物靶点被广泛研究，第二代和第三代抑制剂的临床试验正在进行中。除保守的N端激酶结构域（KD）外，Polo样激酶家族的独特特征在于C端polo-box结构域（PBD）。PBD包含一个磷酸肽结合位点，可识别由其他激酶预激活的底物，并负责将PLK1定位于细胞核内的特定位点（如中心体和动粒）。PBD的另一功能是通过与KD的结构域间相互作用维持PLK1的自抑制状态。对翻译后修饰及PBD-KD结构域关联的研究表明，PLK1调控的关键事件包括磷酸底物结合、T210位点磷酸化以及与Bora蛋白的结合，这些事件可诱导其形成开放活性构象，使结构域间抑制性相互作用失效。最新发现的调控机制还包括单体与二聚体形式的转换，该过程在细胞周期中同样参与PLK1的抑制或激活。研究已鉴定出PLK1的不同寡聚形态（包括与PLK2形成的同源/异源二聚体），这些形态可能在不同情境中发挥特定功能。本综述概述了PLK1抑制的结构与机制研究新进展，及其活化与调控的时空特性要求，同时探讨了Polo样激酶家族其他成员的构象调控机制。PLK1构象调控对细胞周期功能及药物研发具有重要意义，本文对此进行了详细讨论。

原文链接：

Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery