预测的β12-β13环对于抗肿瘤药物福司曲星抑制PP2Aα很重要。
The predicted beta12-beta13 loop is important for inhibition of PP2Acalpha by the antitumor drug fostriecin.
作者信息
Evans D R, Simon J A
机构信息
Program in Molecular Pharmacology, Mailstop D2-100, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA.
出版信息
FEBS Lett. 2001 Jun 1;498(1):110-5. doi: 10.1016/s0014-5793(01)02448-6.
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.
潜在的抗癌药物福司曲星（FOS）是蛋白丝氨酸/苏氨酸磷酸酶PP2A和PP4的强效抑制剂，对PP1的抑制作用较弱。通过酵母中的随机诱变和自动筛选，确定了人PP2Aα中对FOS抑制性结合至关重要的残基。预测的β12-β13环中的C269S取代降低了完整细胞对FOS的敏感性，并使PP2Aα在体外的IC50增加了10倍。将PP2Aα的半胱氨酸-269替换为PP1中的等效残基苯丙氨酸，以及Y267G和G270D取代产生了类似的效果。这些结果为新型蛋白丝氨酸/苏氨酸磷酸酶抑制药物的设计提供了相关信息。
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