5NFU

The structure of the polo-box domain (PBD) of polo-like kinase 1 (Plk1) in complex with LHSpTA peptide

5NFU の概要

• エントリーDOI: 10.2210/pdb5nfu/pdb
• 分子名称: Serine/threonine-protein kinase PLK1, Ac-LEU-HIS-SER-(TPO)-ALA (3 entities in total)
• 機能のキーワード: plk1, pbd1, mitosis, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27848.68

構造登録者

Kunciw, D.L.,Rossmann, M.,De Fusco, C.,Spring, D.R.,Hyvonen, M. (登録日: 2017-03-16, 公開日: 2018-05-16, 最終更新日: 2023-03-08)

主引用文献

Sharma, P.,Mahen, R.,Rossmann, M.,Stokes, J.E.,Hardwick, B.,Huggins, D.J.,Emery, A.,Kunciw, D.L.,Hyvonen, M.,Spring, D.R.,McKenzie, G.J.,Venkitaraman, A.R.
A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation.
Sci Rep, 9:15930-15930, 2019

PubMed 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.

PubMed: 31685831
DOI: 10.1038/s41598-019-50702-2

実験手法

X-RAY DIFFRACTION (1.809 Å)