title: Generation of inhibitor-sensitive protein tyrosine phosphatases via active-site mutations.
abstract: Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of phosphotyrosine, a central control element in mammalian signal transduction. Small-molecule inhibitors that are specific for each cellular PTP would be valuable tools in dissecting phosphorylation networks and for validating PTPs as therapeutic targets. However, the common architecture of PTP active sites impedes the discovery of selective PTP inhibitors. Our laboratory has recently used enzyme/inhibitor-interface engineering to generate selective PTP inhibitors. The crux of the strategy resides in the design of "inhibitor-sensitized" PTPs through protein engineering of a novel binding pocket in the target PTP. "Allele-specific" inhibitors that selectively target the sensitized PTP can be synthesized by modifying broad-specificity inhibitors with bulky chemical groups that are incompatible with wild-type PTP active sites; alternatively, specific inhibitors that serendipitously recognize the sensitized PTP's non-natural pocket may be discovered from panels of "non-rationally" designed compounds. In this review, we describe the current state of the PTP-sensitization strategy, with emphases on the methodology of identifying PTP-sensitizing mutations and synthesizing the compounds that have been found to target PTPs in an allele-specific manner. Moreover, we discuss the scope of PTP sensitization in regard to the potential application of the approach across the family of classical PTPs.
authors.affiliation: Department of Chemistry, Amherst College, Amherst, MA 01002, USA. acbishop@amherst.edu
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Bishop
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Anna Mari
authors.initials: AM
authors.lastname: Lone
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D015202:Protein Engineering / Q000379:methods; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C516607:PTPN1 protein, human; C516649:PTPN2 protein, human; C516656:PTPN3 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D054589:Protein Tyrosine Phosphatase, Non-Receptor Type 3; D017027:Protein Tyrosine Phosphatases