title: A gatekeeper residue for inhibitor sensitization of protein tyrosine phosphatases.
abstract: Allele-specific enzyme inhibitors are powerful tools in chemical biology. However, few general approaches for the discovery of such inhibitors have been described. Herein is reported a method for the sensitization of protein tyrosine phosphatases (PTPs) to small-molecule inhibition. It is shown that mutation of an active-site isoleucine to alanine (I219A) sensitizes PTP1B to inhibition by a class of thiophene-based inhibitors. This sensitization strategy succeeds for both 'orthogonal' inhibitors, designed to be incompatible with wild-type PTP active sites, and previously optimized wild-type PTP inhibitors. The finding that the I219A mutation sensitizes phosphatase domains to a variety of compounds suggests that isoleucine 219 may act as a 'gatekeeper' residue that can be widely exploited for the chemical-genetic analysis of PTP function.
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: Elizabeth R
authors.initials: ER
authors.lastname: Blair
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases