Class IIa histone deacetylases (HDACs) have been considered as potential targets for the treatment of several diseases. Compared to other HDACs, class IIa HDACs have an additional second zinc binding motif. So far, the function of the unique zinc-binding motif is still not very clear. In this work, extensive classical molecular dynamics (MD) simulations were employed to illuminate the conformational change modulated by the unique zinc-binding motif. It has been revealed that the unique zinc-binding motif is a crucial structural stabilization factor in retaining the catalytic activity of the enzyme and the stability of the multi-protein complex, by remotely modulating the active site pocket in a "closed" conformation. Moreover, it is also revealed that the Loop2 motion in HDAC4 is less flexible than that in HDAC7, which opens a new avenue to design selective inhibitors by utilizing the local conformational dynamics difference between the structurally highly similar HDAC4 and HDAC7. Finally, by comparative studies with class I HDACs (HDAC1-3), it is found that the reversible "in-out" conformational transformation of the binding rail (highly conserved both in class I and IIa HDACs) occurs spontaneously in HDAC1-3, whereas the binding rail is trapped in an "in" conformation owing to the strong metal coordination interaction of the unique CCHC zinc-binding motif in class IIa HDACs. Thus, the CCHC zinc-binding motif may be a feasible allosteric site for the development of class IIa-selective inhibitors.