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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism*
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Cell Line
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Crystallography, X-Ray
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Humans
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Models, Molecular
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Oximes / chemistry*
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Peptides / chemistry*
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Peptides / pharmacology*
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Polo-Like Kinase 1
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism*
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Solid-Phase Synthesis Techniques*
Substances
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Cell Cycle Proteins
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Oximes
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Peptides
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases