The interactions between the enzyme-substrate complex of heptaprenyl diphosphate synthase were directly investigated using colloidal probe atomic force microscopy. This enzyme is composed of two dissociable subunits which exhibit a catalytic activity only when they are associated together in the presence of Mg2+ and farnesyl diphosphate (FPP). We observed the adhesive force between the subunits only in the presence of both Mg2+ (0.1 mM) and FPP (15 muM). This is the first direct demonstration of the specific interaction involved in the enzyme reaction.