The predicted β12-β13 loop is important for inhibition of PP2Acα by the antitumor drug fostriecin
- 30 May 2001
- journal article
- Published by Wiley in FEBS Letters
- Vol. 498 (1) , 110-115
- https://doi.org/10.1016/s0014-5793(01)02448-6
Abstract
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 IC50 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 drugsKeywords
This publication has 19 references indexed in Scilit:
- Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signallingBiochemical Journal, 2001
- Importance of the β12-β13 Loop in Protein Phosphatase-1 Catalytic Subunit for Inhibition by Toxins and Mammalian Protein InhibitorsPublished by Elsevier ,1999
- Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecinBritish Journal of Cancer, 1999
- Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promotersFEBS Letters, 1998
- Fostriecin, an antitumor antibiotic with inhibitory activity against serine/threonine protein phosphatases types 1 (PP1) and 2A (PP2A), is highly selective for PP2AFEBS Letters, 1997
- Crystal Structure of the Catalytic Subunit of Human Protein Phosphatase 1 and its Complex with TungstateJournal of Molecular Biology, 1995
- Three-dimensional structure of the catalytic subunit of protein serine/threonine phosphatase-1Nature, 1995
- In Vitro activity of the novel antitumor antibiotic fostriecin (CI-920) in a human tumor cloning assayEuropean Journal of Cancer and Clinical Oncology, 1986
- Novel antitumor agents CI-920,PD113,270 and PD113,271. II. Isolation and characterization.The Journal of Antibiotics, 1983
- Novel antitumor agents CI-920,PD113,270 and PD113,271. I. Taxonomy, fermentation and biological properties.The Journal of Antibiotics, 1983