Chapagai Danda, Strebhardt Klaus, Wyatt Michael D, McInnes Campbell
Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, 02129, USA.
Department of Gynecology, University Hospital, Goethe University, Theodor-Stern-Kai 7-9, Frankfurt am Main, 60596, Germany.
Cancer Gene Ther. 2025 May 16. doi: 10.1038/s41417-025-00907-7.
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.
波罗蛋白样激酶1（PLK1）是有丝分裂的关键调节因子，其过表达通常与癌症患者的低生存率相关，作为一种肿瘤药物靶点，它仍在被广泛研究，目前有多项临床试验在评估第二代和第三代抑制剂。除了保守的N端激酶结构域（KD）外，波罗蛋白样激酶家族的一个独特特征是C端的波罗框结构域（PBD）。PBD包含一个磷酸肽结合位点，该位点可识别由其他激酶引发的底物，此外还负责将PLK1亚细胞定位到细胞核中的特定部位，包括中心体和动粒。PBD的另一个作用是通过与KD的结构域 - 结构域相互作用来维持PLK1的自抑制状态。目前已经获得了对翻译后修饰以及PBD - KD结构域 - 结构域关联的深入了解，结果表明PLK1调节中的关键事件包括磷酸底物结合、T210磷酸化以及与博拉蛋白的结合。这些可以诱导一种开放且活跃的构象，此时结构域 - 结构域抑制性相互作用不再占主导地位。最近描述的进一步调节事件包括单体和二聚体形式之间的互换，这在细胞周期中也可用于抑制或激活PLK1。已经鉴定出PLK1的不同寡聚形式，它们以同二聚体以及与PLK2的异二聚体形式存在，并且可能发挥依赖于环境的作用。本综述概述了最近关于抑制PLK1的结构和机制见解及其激活和调节的时空要求的信息。它还涵盖了对波罗蛋白样激酶家族其他成员构象调节的最新见解。PLK1构象调节对细胞周期功能和药物发现的影响意义重大，因此将进行详细讨论。
