Researchers from the School of Chemical Biology and Biotechnology of Peking University Shenzhen Graduate School have revealed the structural basis of Polo-like kinase 1 (PLK1) inhibition in a new study. The related paper "Structural basis for the inhibition of "Polo-like kinase 1" was published in the journal Nature Structural & Molecular Biology on July 28.
Professor Tao Wang and associate professor Junmin Quan of the School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School are co-corresponding authors of this paper.
Polo-like kinases (PLKs) are a class of serine / threonine protein kinases widely present in eukaryotes. The mammals include PLK1, PLK2, PLK3 and PLK4. They play an important role in all phases of the cell cycle. At present, the research on PLK1 is the most thorough.
Past studies have confirmed that PLK1 is located at different sites along with the process of mitosis, and regulates the processes of mitosis entry, spindle formation and cytokinesis. PLK1 can bind to phosphorylated docking proteins and thus be activated in different spaces to meet its different functions in the cell cycle. PLK1 is also involved in the regulation of G2 and M phase DNA damage monitoring points, which is a necessary condition to re-enter the mitotic phase after DNA damage recovery. In addition, PLK1 is overexpressed in a variety of malignant tumors and is closely related to tumorigenesis. Targeting PLK1 in tumor therapy shows good application prospects and is regarded as a potential cancer therapeutic drug target.
The overall structure of PLK1 includes an N-terminal kinase domain (KD), a C-terminal Polo box domain (PBD domain) and an intermediate connection region. The PBP domain regulates the localization of Polo-like kinases in cells and protein-protein interactions. The kinase domain of PLK1 includes the nuclear localization signal region (NLS), the destruction box after mitosis (D-box), and a section of T-loop, which is closely related to ATP binding and enzyme activity. In addition, this domain is also related to the subcellular localization of PLK1 and its recruitment to protein substrates. Under normal circumstances, the kinase domain binds to PBD and exists in a form similar to mutual inhibition, but the molecular mechanism of this self-inhibition is currently unclear.
In this article, the researchers reported that the resolution of 2.3- ?, the zebrafish (Danio rerio) PLK1 KD and PBD domains, and Drosophila melanogaster microtubule-associated protein 205 (Map205PBM) constitute a PBD binding motif The crystal structure of the complex. They analyzed the overall structure of KD-PBD-Map205PBM composite, the details of KD-PBD interaction, and the details of PBD-Map205PBM interaction. The results show that PBD binds and fixes the Hinge area of ​​KD, reducing the flexibility of KD. Subsequently, the researchers used GST pull-down experiments and pseudo-phosphorylated mutants to draw a multi-level regulation model of PLK1, and confirmed that PLK1 can be partially or completely activated by phosphorylation and phosphopeptide binding.
This structure provides a framework for understanding the self-inhibition mechanism of PLK1 and clarifies the molecular mechanism of PLK activation through phosphorylation or phosphopeptide binding.
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