Engineering non-natural inhibitor sensitivity in protein tyrosine phosphatase H1.
Protein tyrosine phosphatase H1, a member of the ubiquitous protein tyrosine phosphatase (PTP) superfamily of enzymes, is an important signaling molecule, mutant forms of which have been found in human colorectal cancers. Selective PTPH1 inhibitors would be valuable tools for investigating PTPH1's roles in cellular regulation. However, no PTPH1-specific inhibitors are known. To identify target-selective inhibitors of human PTPH1, we have redesigned a PTPH1/inhibitor interface. Structure-based protein design was used to identify two amino-acid residues, isoleucine 846 and methionine 883, that control PTPH1's sensitivity to oxalylaminoindole PTP inhibitors. Mutation of residues 846 and 883 to alanine and glycine, respectively, conferred novel inhibitor sensitivity onto PTPH1. From a small panel of putative inhibitors, compounds that potently and selectively target the inhibitor-sensitized PTPH1 mutants were identified.
Blair
Elizabeth R
ER
Department of Chemistry, Amherst College, Amherst, MA 01002, USA.
Hoffman
Hillary E
HE
Bishop
Anthony C
AC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D015202:Protein Engineering; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
D017931:DNA Primers; D004791:Enzyme Inhibitors; D017027:Protein Tyrosine Phosphatases