Actin is the primary cellular receptor of bistramide a

Bistramide A (1) is a marine natural product with broad, potent antiproliferative effects. Bistramide A has been reported to selectively activate protein kinase C (PKC) δ, leading to the view that PKCδ is the principal mediator of antiproliferative activity of this natural product. Contrary to this observation, we established that bistramide A binds PKCδ with low affinity, does not activate this kinase in vitro and does not translocate GFP-PKCδ. Furthermore, we identified actin as the cellular receptor of bistramide A. We report that bistramide A disrupts the actin cytoskeleton, inhibits actin polymerization, depolymerizes filamentous F-actin in vitro and binds directly to monomeric G-actin in a 1:1 ratio with a K_d of 7 nM. We also constructed a fully synthetic bistramide A–based affinity matrix and isolated actin as a specific bistramide A–binding protein. This activity provides a molecular explanation for the potent antiproliferative effects of bistramide A, identifying it as a new biochemical tool for studies of the actin cytoskeleton and as a potential lead for development of a new class of antitumor agents.