Polo-like kinase 1 (PLK1) (PLK1)

Polo-like kinase 1 (PLK1) is a critical serine/threonine kinase that serves as a master regulator of the eukaryotic cell cycle, particularly during the transition into and progression through mitosis (UniProt: P53350). It governs essential processes such as centrosome maturation, bipolar spindle formation, and cytokinesis. The Polo-box domain (PBD) at the C-terminus of PLK1 is a unique phosphopeptide-binding module that facilitates the enzyme's localization to specific subcellular structures by recognizing phosphorylated motifs on scaffold proteins (PubMed: 19249352). The pyrrolidine-binding pocket within the PBD is a key structural feature that accommodates the proline residue of the consensus S-[pS/pT]-P motif found in PLK1 substrates (PubMed: 18483318). Targeting this pocket with small molecules or peptidomimetics offers a strategy to inhibit PLK1 through the disruption of protein-protein interactions, providing a potentially more selective therapeutic approach than traditional ATP-competitive inhibitors (PubMed: 24511993). PLK1 is frequently overexpressed in a wide variety of human cancers and is strongly associated with poor prognosis and increased tumor grade. Consequently, the PBD and its pyrrolidine-binding pocket have become high-priority targets for the development of next-generation antineoplastic agents designed to induce mitotic arrest and apoptosis in malignant cells.

Other names

PLK-1Serine/threonine-protein kinase PLK1STPK13Polo-box domainPBDPLK1 PBD pyrrolidine pocket

Inhibition of protein-protein interactions (PPI) by binding to the Polo-box domain (PBD), specifically the pyrrolidine-binding pocket, which prevents the recruitment of PLK1 to its phosphorylated substrates and disrupts its subcellular localization during mitosis.