The predicted β12-β13 loop is important for inhibition of PP2Acα by the antitumor drug fostriecin

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 PP2Ac alpha important for inhibitory FOS binding. A C269S substitution in the predicted beta 12-beta 13 loop decreased the FOS sensitivity of intact cells and increased the IC50 of PP2Ac alpha by 10-fold in vitro, Changing PP2Ac alpha 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. (C) 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.