There is a structurally diverse group of natural toxins, includin okadaic acid, calyculin, microcystin LR, and tautomycin, that exert their cytotoxic effects by inhibiting the serine-threonine protein phosphatases PP1 and PP2A. This activity dramatically increases the phosphorylation state of a variety of proteins within the cell, a process that can have profound effects such as the disastrous disruption of intracellular signal trafficking, the deposition of proteinacious plaque and fibrils, and even unregulated cellular proliferation. The compounds themselves are therefore not only acute hepatotoxins, but also tumor promotors. Interestingly, despite the dissimilarities of the toxins structures, these compounds are competitive inhibitors, namely, their PP1/PP2A binding sites overlap. Because as a group they inhibit PP1 and PP2A quite potently and specifically relative to other known phosphatases such as PP2B (calcineurin), PP2C, and the tyrosine phosphatases, several members of this group have become important probes of intracellular signalling pathways. However, there are problems of poor selectivity between the two phosphatases, which can result in ambiguous results when attempts are being made to define the separate roles of PP1 and PP2A in a given process. In particular, there is no known membrane-permeable small molecule that inhibits PP1 with good selectivity. A recently published X-ray crystal structure of a PP1-microcystin LR complex provides a unique opportunity to explore binding interactions of all these inhibitors with both PP1 and PP2A, and to develop new selective inhibitors based on these natural products.
