ArticleScientific reports2019
A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- Monoclonal Antibodies Accessing the Cytosol of Living Cells and Binding to Polo-Like Kinase 1 Interdomain Linker Affect Mitotic Behavior.Chembiochem : a European journal of chemical biology · 2026Article
- Molecular anatomy of PLK1 master docking motifs.Nature communications · 2026Article
- A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English.Journal of visualized experiments : JoVE · 2026Article
- A coordinated kinase and phosphatase network regulates Stu2 recruitment to yeast kinetochores.The Journal of cell biology · 2025Article
- Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery.Cancer gene therapy · 2025Review
- Plastics in the environment in the context of UV radiation, climate change and the Montreal Protocol: UNEP Environmental Effects Assessment Panel, Update 2023.Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology · 2024Article
- Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design.International journal of molecular sciences · 2023Article
- Specific inhibition of an anticancer target, polo-like kinase 1, by allosterically dismantling its mechanism of substrate recognition.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors.Cells · 2023Review
- Structural Optimization and Anticancer Activity of Polo-like Kinase 1 (Plk1) Polo-Box Domain (PBD) Inhibitors and Their Prodrugs.ACS pharmacology & translational science · 2023Article
- Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs.The Biochemical journal · 2022Review
- ProxyBind: A compendium of binding sites for proximity-induced pharmacology.Computational and structural biotechnology journal · 2022Article
- Dynamic regulation of mitotic ubiquitin ligase APC/C by coordinated Plx1 kinase and PP2A phosphatase action on a flexible Apc1 loop.The EMBO journal · 2021Article
- Nonpeptidic, Polo-Box Domain-Targeted Inhibitors of PLK1 Block Kinase Activity, Induce Its Degradation and Target-Resistant Cells.Journal of medicinal chemistry · 2021Article
- Kinetochore phosphatases suppress autonomous Polo-like kinase 1 activity to control the mitotic checkpoint.The Journal of cell biology · 2020Article
- Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1.Journal of medicinal chemistry · 2020Article
- Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.ChemMedChem · 2020Article
- Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.ACS omega · 2020Article
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
The human polo-like kinase PLK1 coordinates mitotic chromosome segregation by phosphorylating multiple chromatin- and kinetochore-binding proteins. How PLK1 activity is directed to specific substrates via phosphopeptide recognition by its carboxyl-terminal polo-box domain (PBD) is poorly understood. Here, we combine molecular, structural and chemical biology to identify a determinant for PLK1 substrate recognition that is essential for proper chromosome segregation. We show that mutations ablating an evolutionarily conserved, Tyr-lined pocket in human PLK1 PBD trigger cellular anomalies in mitotic progression and timing. Tyr pocket mutations selectively impair PLK1 binding to the kinetochore phosphoprotein substrate PBIP1, but not to the centrosomal substrate NEDD1. Through a structure-guided approach, we develop a small-molecule inhibitor, Polotyrin, which occupies the Tyr pocket. Polotyrin recapitulates the mitotic defects caused by mutations in the Tyr pocket, further evidencing its essential function, and exemplifying a new approach for selective PLK1 inhibition. Thus, our findings support a model wherein substrate discrimination via the Tyr pocket in the human PLK1 PBD regulates mitotic chromosome segregation to preserve genome integrity.
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