title: Identification of high affinity polo-like kinase 1 (Plk1) polo-box domain binding peptides using oxime-based diversification.
abstract: 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.
authors.affiliation: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Fa
authors.initials: F
authors.lastname: Liu
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Qian
authors.forename: Dan
authors.initials: D
authors.lastname: Lim
authors.forename: Andrej
authors.initials: A
authors.lastname: Scharow
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
authors.forename: Michael B
authors.initials: MB
authors.lastname: Yaffe
authors.forename: Kyung S
authors.initials: KS
authors.lastname: Lee
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010091:Oximes / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D060327:Solid-Phase Synthesis Techniques; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D010091:Oximes; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1