Three representative protomers within a VCP hexamer are shown in the model. The D2 in the central protomer (N) is highlighted. The conformational changes observed in the four nucleotide states apo, ATP, ATP‡ and ADP over a cycle of ATP hydrolysis are schematically represented. The largest conformational changes occur between the preactivated states i and ii (apo and ATP) and the activated states iii and iv (ATP‡ and ADP). (i) In the apo state, the D2 domain (dark yellow) and D1-D2 linker (orange) are in a disordered state. (ii) Upon ATP binding, only small conformational changes occur. (iii) ATP interactions with D2 elements induce major conformational changes that result in an overall more ordered D2 and D1-D2 linker (orange) in the activated ATP state (ATP‡; red), with formation of the allosteric inhibitor binding site (violet). (iv) ATP hydrolysis leading to the ADP state induces a repositioning of the arginine finger (indicated by the dotted arrow) that in turn assists γ-phosphate release in the N + 1 protomer. Binding of allosteric inhibitors, which most likely occurs through interactions with the ISS motif, hampers the movement of the arginine finger toward the γ-phosphate, thus preventing ATP hydrolysis propagation and freezing D2 in the ADP-bound state. 