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

被引:24
作者
Evans, DRH [1 ]
Simon, JA [1 ]
机构
[1] Fred Hutchinson Canc Res Ctr, Program Mol Pharmacol, Seattle, WA 98109 USA
关键词
fostriecin; phosphatase; protein serine/threonine phosphatase 2A; cancer; yeast; drug;
D O I
10.1016/S0014-5793(01)02448-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:110 / 115
页数:6
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