Identification of High Affinity Polo-like Kinase 1 (Plk1) Polo-box Domain Binding Peptides Using Oxime-Based Diversification
journal contributionposted on 18.05.2012 by Fa Liu, Jung-Eun Park, Wen-Jian Qian, Dan Lim, Andrej Scharow, Thorsten Berg, Michael B. Yaffe, Kyung S. Lee, Terrence R. Burke
Any type of content formally published in an academic journal, usually following a peer-review process.
In 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.