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Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel

  1. Author:
    Liu, F.
    Park, J. E.
    Qian, W. J.
    Lim, D.
    Graber, M.
    Berg, T.
    Yaffe, M. B.
    Lee, K. S.
    Burke, T. R.

  2. Author Address

    [Liu, F; Qian, WJ; Burke, TR] NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21701 USA. [Park, JE; Lee, KS] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lim, D; Yaffe, MB] MIT, Ctr Canc Res, Dept Biol & Biol Engn, Cambridge, MA 02139 USA. [Graber, M; Berg, T] Univ Leipzig, Inst Organ Chem, Leipzig, Germany.;Liu, F (reprint author), NCI, Biol Chem Lab, Mol Discovery Program, Ctr Canc Res, Frederick, MD 21701 USA;kyunglee@mail.nih.gov tburke@helix.nih.gov
    1. Year: 2011
    2. Date: Sep
  2. Journal: Nature Chemical Biology
    1. 7
    2. 9
    3. Pages: 595-601
  4. Type of Article: Article
  5. ISSN: 1552-4450
  1. Abstract:

    We obtained unanticipated synthetic byproducts from alkylation of the delta(1) nitrogen (N3) of the histidine imidazole ring of the polo-like kinase-1 (Plk1) polo-box domain (PBD)-binding peptide PLHSpT. For the highest-affinity byproduct, bearing a C(6)H(5)(CH(2))(8)- group, a Plk1 PBD cocrystal structure revealed a new binding channel that had previously been occluded. An N-terminal PEGylated version of this peptide containing a hydrolytically stable phosphothreonyl residue (pT) bound the Plk1 PBD with affinity equal to that of the non-PEGylated parent but showed markedly less interaction with the PBDs of the two closely related proteins Plk2 and Plk3. Treatment of cultured cells with this PEGylated peptide resulted in delocalization of Plk1 from centrosomes and kinetochores and in chromosome misalignment that effectively induced mitotic block and apoptotic cell death. This work provides insights that might advance efforts to develop Plk1 PBD-binding inhibitors as potential Plk1-specific anticancer agents.

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External Sources

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  2. DOI: 10.1038/nhembio.614
  3. View record in Web of Science®
  4. WOS: 000294381400009

Library Notes

  1. Fiscal Year: FY2011-2012
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