Fig. 2. Model of the V-type H⁺ ATPase expressed in a eukaryotic cell membrane. (A) Molecular model. The peripheral V₁ complex consists of eight different subunits identified with capital letters A-H. Subunit G exists as the dimer G₂. The integral membrane V₀ complex consists of at least four different subunits identified with small letters (a,c,d,e). Subunit c and its isoforms c' and c'' form a H⁺-binding rotor ring. Actin binds to subunits B (Holliday et al., 2000) and C (Vitavska et al., 2003). (B) Mechanistic model. V₀ and V₁ complexes are joined by a central rotating shaft (subunits D,F) and a peripheral stationary shaft (subunits C,E,G,H,a). The central shaft of the V₁ complex and the c-ring of the V₀ complex form the rotor (red). The remainder is considered the stator (grey). Hydrolysis of ATP brings about rotation of the central shaft together with the c-ring of the V₀ complex. Subunit a hypothetically provides two H⁺ half channels that are offset. Rotation of the c-ring conveys H⁺ from the inner half channel to the outer half channel via an intermediary H⁺ binding step to one subunit c. The pleomacrolides bafilomycin and concanomycin, as well as the recently discovered macrolactone archazolid, are highly specific inhibitors that bind to the c subunits in the V₀ complex (Huss et al., 2002; Huss et al., 2005). Adapted from various sources (Inoue and Forgac, 2005; Murata et al., 2005; Wilkens et al., 2005).