Today I will talk about microcystin and its mode of action. This molecule is one of my all-time favourites because of its unique reactivity. Below you can see a view I created using 1FJM entry from the Protein Databank. This picture shows the electrophilic warhead of microcystin and identifies the surface-exposed nucleophilic Cys-273 residue of PP1 phosphatase. This cysteine irreversibly interacts with the electrophilic acrylamide portion of microcystin.
My lab has been after some complex peptide macrocycles equipped with electrophilic aziridine residues. We do not yet have any significant stories to tell in our efforts to covalently inhibit cysteine-bearing protein targets, but we do have the methodological makings of an interesting approach in collaboration with Ben Cravatt of Scripps. So far our molecules seem to be inert against cysteines, which is somewhat of a surprise, yet gives us confidence that we might eventually find something really selective. Back to microcystin: this nanomolar phosphatase inhibitor is a nasty beast that was isolated from cyanobacteria. The corresponding blue-green algae contaminate drinking water and have long been known to be the cause of animal deaths.