Polo-like kinases (Plks) are a conserved subfamily of Ser/Thr protein kinases that play pivotal roles in cellular proliferation. Since Plk1 overexpression is closely associated with oncogenesis, Plk1 is considered an attractive target for anti-cancer therapy. The polo-box domain (PBD) uniquely found in the C-terminal non-catalytic region of Plks forms a phosphoepitope-binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interacted with the PBD of Plk1, but not the two closely-related Plk2 and Plk3, with a high affinity. Comparative binding studies and analyses of the crystal structures of the Plk1 PBD in complex with a minimal phosphopeptide (PLHSpT), its derivative PPHSpT, or no peptide, revealed that the C-terminal SpT dipeptide functions as a high affinity anchor, whereas the N-terminal PLH residues are critical for providing both specificity and affinity to the PBD. Glycerol molecule and sulfate anion are functional equivalents to the Ser and the phosphate moiety of the phospho-Thr, respectively. Testing of a minimal phospho-Thr mimetic peptide demonstrated that inhibition of the PBD of Plk1 is sufficient to induce a mitotic arrest and apoptosis. Thus, the mode of PLHSpT binding to the PBD may provide an important template for designing anti-Plk1 therapeutic agents.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Park, Jung-Eun; Hymel, David; Burke Jr, Terrence R et al. (2017) Current progress and future perspectives in the development of anti-polo-like kinase 1 therapeutic agents. F1000Res 6:1024
Park, Jung-Eun; Kim, Tae-Sung; Kim, Bo Yeon et al. (2015) Selective blockade of cancer cell proliferation and anchorage-independent growth by Plk1 activity-dependent suicidal inhibition of its polo-box domain. Cell Cycle 14:3624-34
Qian, Wen-Jian; Park, Jung-Eun; Grant, Robert et al. (2015) Neighbor-directed histidine N (?)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles. Biopolymers 104:663-73
Lee, Kyung S; Burke Jr, Terrence R; Park, Jung-Eun et al. (2015) Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy. Trends Pharmacol Sci 36:858-877
Kim, Ju Hee; Ku, Bonsu; Lee, Kyung S et al. (2015) Structural analysis of the polo-box domain of human Polo-like kinase 2. Proteins :
Jia, Jia-Lin; Han, Young-Hyun; Kim, Hak-Cheol et al. (2015) Structural basis for recognition of Emi2 by Polo-like kinase 1 and development of peptidomimetics blocking oocyte maturation and fertilization. Sci Rep 5:14626
Qian, Wen-Jian; Park, Jung-Eun; Lim, Dan et al. (2014) Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high Plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in HeLa cells. Biopolymers 102:444-55
Srinivasrao, Ganipisetti; Park, Jung-Eun; Kim, Sungmin et al. (2014) Design and synthesis of a cell-permeable, drug-like small molecule inhibitor targeting the polo-box domain of polo-like kinase 1. PLoS One 9:e107432
Kim, Sun-Ok; Sakchaisri, Krisada; Thimmegowda, N R et al. (2013) STK295900, a dual inhibitor of topoisomerase 1 and 2, induces G(2) arrest in the absence of DNA damage. PLoS One 8:e53908
Qian, Wenjian; Park, Jung-Eun; Liu, Fa et al. (2013) Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position. Bioorg Med Chem 21:3996-4003

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