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The predicted β12–β13 loop is important for inhibition of PP2Acα by the antitumor drug fostriecin
Author(s) -
Evans David R.H,
Simon Julian A
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02448-6
Subject(s) - protein phosphatase 2 , inhibitory postsynaptic potential , chemistry , phosphatase , in vitro , drug , biochemistry , phenylalanine , mutagenesis , pharmacology , biology , enzyme , amino acid , mutation , gene , endocrinology
The potential anticancer agent fostriecin (FOS) is a potent inhibitor of the protein Ser/Thr phosphatases PP2A and PP4 and a weaker inhibitor of PP1. Random mutagenesis and automated screening in yeast identified residues in human PP2Acα important for inhibitory FOS binding. A C269S substitution in the predicted β12–β13 loop decreased the FOS sensitivity of intact cells and increased the IC 50 of PP2Acα by 10‐fold in vitro. Changing PP2Acα Cys‐269 to phenylalanine, the equivalent residue in PP1, and the Y267G and G270D substitutions caused a similar effect. The results provide information relevant to the design of novel protein Ser/Thr phosphatase inhibitory drugs.