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Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1

  1. Author:
    Yun, S. M.
    Moulaei, T.
    Lim, D.
    Bang, J. K.
    Park, J. E.
    Shenoy, S. R.
    Liu, F.
    Kang, Y. H.
    Liao, C. Z.
    Soung, N. K.
    Lee, S.
    Yoon, D. Y.
    Lim, Y.
    Lee, D. H.
    Otaka, A.
    Appella, E.
    McMahon, J. B.
    Nicklaus, M. C.
    Burke, T. R.
    Yaffe, M. B.

  2. Author Address

    Yun, Sang-Moon, Park, Jung-Eun, Kang, Young H.; Soung, Nak-Kyun, Lee, Sunhee, Lee, Dong-Hee, Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Moulaei, Tinoush, Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Lim, Dan, Yaffe, Michael B.] MIT, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA. [Lim, Dan, Yaffe, Michael B.] MIT, Ctr Canc Res, Dept Biol Engn, Cambridge, MA 02139 USA. [Bang, Jeong K.] Korea Basic Sci Inst, Pusan, South Korea. [Shenoy, Shilpa R.] NCI, Mol Targets Dev Program, SAIC Frederick, Frederick, MD 21701 USA. [Liu, Fa, Liao, Chenzhong, Nicklaus, Marc C.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Lee, Sunhee, Yoon, Do-Young, Lim, Yoongho] Konkuk Univ, Dept Biosci & Biotechnol, Seoul, South Korea. [Lee, Dong-Hee] Univ Seoul, Dept Life Sci, Seoul, South Korea. [Otaka, Akira] Univ Tokushima, Grad Sch Pharmaceut Sci, Inst Hlth Biosci, Tokushima 770, Japan. [Appella, Ettore] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [McMahon, James B.] NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21701 USA.
    1. Year: 2009
  2. Journal: Nature Structural & Molecular Biology
    1. 16
    2. 8
    3. Pages: 876-U104
  4. Type of Article: Article
  1. Abstract:

    Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.

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  2. DOI: 10.1038/nsmb.1628
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