Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel
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Yaffe_Serendipitous alkylation.pdf
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Author(s)
Liu, Fa
Park, Jung-Eun
Qian, Wen-Jian
Gräber, Martin
Berg, Thorsten
Lee, Kyung S.
Lim, Daniel Cham-Chin
Yaffe, Michael B
Burke, Terrence R.
Date Issued
July 2011
Journal
Nature Chemical Biology
Publisher
Nature Publishing Group
Citation
Liu, Fa et al. “Serendipitous Alkylation of a Plk1 Ligand Uncovers a New Binding Channel.” Nature Chemical Biology 7.9 (2011): 595–601.
Version
Author's final manuscript
Abstract
We obtained unanticipated synthetic byproducts from alkylation of the δ[superscript 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[subscript 6]H[subscript 5](CH[subscript 2])[subscript 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/nchembio.614
