title: Phosphatase-Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo-Box Domain of Polo-like Kinase 1.
abstract: (2S,3R)-2-Amino-3-methyl-4-phosphonobutanoic acid (Pmab) is a phosphatase-stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagent. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R center. When incorporated into our peptidomimetic scaffold, these new Pmab analogues exhibit Plk1 PBD-binding affinities that are several-fold higher than Pmab, yet retain good selectivity for Plk1 relative to the PBDs of Plk2 and Plk3. These findings will significantly impact the future development of PBD-binding inhibitors, as well as ligands directed against a broad spectrum of pThr-dependent processes.
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Frederick, MD, 21702, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hymel
authors.affiliation: Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Frederick, MD, 21702, USA.
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D056004:Molecular Dynamics Simulation; D019606:Phosphoamino Acids / Q000737:chemistry* / Q000378:metabolism; D010769:Phosphothreonine / Q000737:chemistry; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D019606:Phosphoamino Acids; D010769:Phosphothreonine; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1
keywords: phosphatases; phosphothreonine; polo-box domain; polo-like kinase 1