Identification of High Affinity Polo-like Kinase 1 (Plk1) Polo-box Domain Binding Peptides Using Oxime-Based Diversification
Author(s)Liu, Fa; Park, Jung-Eun; Qian, Wen-Jian; Scharow, Andrej; Berg, Thorsten; Yaffe, Michael B.; Lee, Kyung S.; Burke, Terrence R., Jr.; Lim, Daniel Cham-Chin; ... Show more Show less
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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.
DepartmentDavid H. Koch Institute for Integrative Cancer Research at MIT; Massachusetts Institute of Technology. Department of Biological Engineering; Massachusetts Institute of Technology. Department of Biology
ACS Chemical Biology
American Chemical Society (ACS)
Liu, Fa, Jung-Eun Park, Wen-Jian Qian, Dan Lim, Andrej Scharow, Thorsten Berg, Michael B. Yaffe, Kyung S. Lee, and Terrence R. Burke. “Identification of High Affinity Polo-Like Kinase 1 (Plk1) Polo-Box Domain Binding Peptides Using Oxime-Based Diversification.” ACS Chemical Biology 7, no. 5 (May 18, 2012): 805–810.
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