Actin-targeting natural products: structures, properties and mechanisms of action

Abstract

Natural small-molecule inhibitors of actin cytoskeleton dynamics have long been recognized as valuable molecular probes for dissecting complex mechanisms of cellular function. More recently, their potential use as chemotherapeutic drugs has become a focus of scientific investigation. The primary focus of this review is the molecular mechanism by which different actin-targeting natural products function, with an emphasis on structural considerations of toxins for which high-resolution structural information of their interaction with actin is available. By comparing the molecular interactions made by different toxin families with actin, the structural themes of those that alter filament dynamics in similar ways can be understood. This provides a framework for novel synthetic-compound designs with tailored functional properties that could be applied in both research and clinical settings.

Direct interaction of Cucurbitacin E isolated from Alsomitra macrocarpa to actin filament

“…Many actin-targeting molecules were obtained from marine organisms, mushrooms, and molds, and these molecules are classified into two prominent types (Allingham et al 2006); the first ones are actin filament destabilizers such as cytochalasins and latrunculins, and the other ones are actin filament stabilizers such as jasplakinolide and phalloidin. In the cultured mammalian cells, both cause actin filament aggregation (Hoehn et al 1973;Usui et al 2004).…”

Truncated Latrunculins as Actin Inhibitors Targeting Plasmodium falciparum Motility and Host Cell Invasion

“…The latrunculins specifically bind near the ATP binding cleft between subdomains D2 and D4 of the actin monomer 10 and thereby sequester actin away from the free cytosolic pool in a fashion similar to that of monomer sequestering proteins. 15 We set out to identify the key differences in the latrunculin-bound binding pocket of the human and the P. falciparum actin in order to design a parasite-specific latrunculin-like compound.…”

“…[7][8][9] Actin can reversibly polymerise between its monomeric (G-actin) and filamentous (F-actin) form. 10,11 Importantly, actin dynamics is an essential element involved in the cell motility and host cell invasion of malarial parasites. 11,12 Malaria disease occurs during the blood-stage of infection, when the merozoite form of parasites invade red blood cells and replicate inside them, and actin is crucial in this invasion process.…”

“…10 Thus, compounds that selectively target such sites, with a preference for residues characterising the P. falciparum actin over human actin, could be used to selectively target parasite actin-dependent processes, arresting cell motility and invasion and, as such, present a potentially potent therapeutic approach to stopping malaria disease. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Latrunculins (Figure 1) are macrolides initially isolated from the marine sponge Negombata magnifica found in the red sea 10,13 and are known to bind to the G-actin monomer in a 1:1 complex blocking the ability of actin to polymerize into the growing filament. 14 …”

Developmental Biology of Neoplastic Growth

“…Crystal structures of complexes between G-actin and kabiramide C, jaspisamide A, and halichondramide have been solved ; for review see Allingham et al 2006). These toxins interact with residues between subdomains I and III in actin monomer as does gelsolin .…”