Serendipitous alkylation of a Plk1 ligand uncovers a new binding channel.

TitleSerendipitous alkylation of a Plk1 ligand uncovers a new binding channel.
Publication TypeJournal Article
Year of Publication2011
AuthorsLiu, F, Park, J-E, Qian, W-J, Lim, D, Gräber, M, Berg, T, Yaffe, MB, Lee, KS, Burke, TR
JournalNat Chem Biol
Date Published2011 Sep
KeywordsAlkylation, Antineoplastic Agents, Apoptosis, Binding Sites, Cell Cycle Proteins, Centrosome, HeLa Cells, Histidine, Humans, Kinetochores, Peptides, Phosphothreonine, Polyethylene Glycols, Protein Binding, Protein Structure, Tertiary, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins

We obtained unanticipated synthetic byproducts from alkylation of the δ(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.

Alternate JournalNat. Chem. Biol.
PubMed ID21765407
PubMed Central IDPMC3158281
Grant ListCA112967 / CA / NCI NIH HHS / United States
GM60594 / GM / NIGMS NIH HHS / United States
GM68762 / GM / NIGMS NIH HHS / United States
Z01 BC006198-18 / BC / NCI NIH HHS / United States
Z01 BC006198-19 / BC / NCI NIH HHS / United States
Z99 CA999999 / CA / NCI NIH HHS / United States