title: Allele-specific inhibitors of protein tyrosine phosphatases.
abstract: Protein tyrosine phosphatases (PTPs) are critical cell-signaling molecules. Inhibitors that are selective for individual PTPs would be valuable tools for dissecting complicated phosphorylation networks. However, the common architecture of PTP active sites impedes the discovery of such compounds. To achieve target selectivity, we have redesigned a PTP/inhibitor interface. Site-directed mutagenesis of a prototypical phosphatase, PTP1B, was used to generate "inhibitor-sensitized" PTPs. The PTP1B mutants were targeted by modifying a broad specificity PTP inhibitor with chemical groups that are sterically incompatible with wild-type PTP active sites. From a small panel of putative inhibitors, compounds that selectively inhibit Ile219Ala PTP1B over the wild-type enzyme were identified. Importantly, the corresponding mutation also conferred novel inhibitor sensitivity to T-cell PTP, suggesting that a readily identifiable point mutation can be used to generate a variety of inhibitor-sensitive PTPs.
authors.affiliation: Department of Chemistry, Amherst College, Amherst, Massachusetts 01002, USA.
authors.forename: Hillary E
authors.initials: HE
authors.lastname: Hoffman
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Blair
authors.forename: James E
authors.initials: JE
authors.lastname: Johndrow
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Bishop
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015202:Protein Engineering; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases