The predicted beta12-beta13 loop is important for inhibition of PP2Acalpha 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 PP2Acalpha important for inhibitory FOS binding. A C269S substitution in the predicted beta12-beta13 loop decreased the FOS sensitivity of intact cells and increased the IC(50) of PP2Acalpha by 10-fold in vitro. Changing PP2Acalpha 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.
Evans
D R
DR
Program in Molecular Pharmacology, Mailstop D2-100, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA. drhevans@fhcrc.org
Simon
J A
JA
D000475:Alkenes / Q000494:pharmacology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003545:Cysteine / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011090:Polyenes; D017433:Protein Structure, Secondary; D011753:Pyrones; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics
D000475:Alkenes; D000970:Antineoplastic Agents; D011090:Polyenes; D011753:Pyrones; D012694:Serine; D010749:Phosphoprotein Phosphatases; D003545:Cysteine; C040313:fostriecin