Small Molecules/Drugs that Bind to Actin[Edit]
Although actin-binding drugs have proven ineffective as pharmacological treatments due to poor uptake into cells or specific adverse effects, they are still widely used in research for their ability to alter actin filament dynamics. Toxins such as phalloidins, cytochalasins, latrunculin A, and jasplakinolide are naturally occurring small molecules that bind to actin and alter its polymerization.
As experimental agents, the phalloidins are limited by their inability to permeate the cellular membrane of living cells. Despite this their effect on polymerization differs from other commonly used agents and therefore the phalloidins are valuable agents for in vitro experiments.
Phalloidins bind to actin filaments at a ratio of one molecule for either one or two actin protomers and essentially lock adjacent actin subunits together. This shifts the equilibrium to favour filament formation over filament disassembly. As filament formation is normally a balance between monomer association and filament dissociation, blocking the latter step reduces the critical concentration of free monomers required to maintain filament elongation. (reviewed in [1]).
Phalloidins bind to actin filaments at a ratio of one molecule for either one or two actin protomers and essentially lock adjacent actin subunits together. This shifts the equilibrium to favour filament formation over filament disassembly. As filament formation is normally a balance between monomer association and filament dissociation, blocking the latter step reduces the critical concentration of free monomers required to maintain filament elongation. (reviewed in [1]).
Latrunculin A
Latrunculin A is a natural toxin purified from the red sea sponge Latrunculia magnifica. It was initially found to inhibit actin polymerization and disrupt the arrangement of F-actin within non-muscle cells. Further studies identified a 1:1 binding ratio between Latrunculin A and G-actin monomers [2]. Through the sequestration of actin monomers, polymerization is prevented and thus filament disassembly is promoted [3]. Studies investigating the binding mechanism of Latrunculin A to actin have revealed its presence does not inhibit profilin binding, suggesting the drug binds at a different site. It has been postulated that the drug binds at the ATP binding site, as it was shown to inhibit nucleotide exchange on actin subunits [4]. Binding of thymosin β4 to actin however is also inhibited by Latrunculin A, despite its binding site lying more than 20Å from the nucleotide binding site. This suggests either an allosteric effect on the nucleotide binding site, or the thymosin binding site, with the actual binding site remaining unclear [4].
Cytochalasin D
Cytochalasin D is the most commonly used drug from the cytochalasin class of small molecules. Various effects were reported from this class of compounds, including inhibition of monosaccaride transport across the cellular membrane [5], however its effect on actin polymerization is the most prominent.
Unlike Latrunculin A, the cytochalasins bind actin filaments rather than G-actin monomers. Binding occurs at a ratio of one molecule per filament, and binding occurs selectively at the barbed end of the filaments. This effectively blocks association (and dissociation) of actin monomers at the barbed end, halting further elongation of filaments [1].
Unlike Latrunculin A, the cytochalasins bind actin filaments rather than G-actin monomers. Binding occurs at a ratio of one molecule per filament, and binding occurs selectively at the barbed end of the filaments. This effectively blocks association (and dissociation) of actin monomers at the barbed end, halting further elongation of filaments [1].