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Identification of High Affinity Polo-like Kinase 1 (Plk1) Polo-box Domain Binding Peptides Using Oxime-Based Diversification
journal contribution
posted on 2012-05-18, 00:00 authored by Fa Liu, Jung-Eun Park, Wen-Jian Qian, Dan Lim, Andrej Scharow, Thorsten Berg, Michael
B. Yaffe, Kyung S. Lee, Terrence R. BurkeIn an effort to develop improved binding antagonists
of the polo-like
kinase 1 (Plk1) polo-box domain (PBD), we optimized interactions of
the known high affinity 5-mer peptide PLHSpT using oxime-based post
solid-phase peptide diversification of the N-terminal
Pro residue. This allowed us to achieve up to two orders of magnitude
potency enhancement. An X-ray crystal structure of the highest affinity
analogue in complex with Plk1 PBD revealed new binding interactions
in a hydrophobic channel that had been occluded in X-ray structures
of the unliganded protein. This study represents an important example
where amino acid modification by post solid-phase oxime ligation can
facilitate the development of protein–protein interaction inhibitors
by identifying new binding pockets that would not otherwise be accessible
to coded amino acid residues.