Zinc cofactor in human histone deacetylase 8: Requirement for function and opportunity for drug discovery

HDAC8 (histone deacetylase 8), a class I HDAC, is a promising target for different disorders: X-linked intellectual disability, fibrotic disease, cancer, and several neuropathological diseases. The structural and functional similarity between HDACs hinders the development of selective HDAC8 inhibitors. To date, no drugs based on competitive inhibition have been approved. In order to identify weaknesses in HDAC8 amenable to drug discovery, we report here a comprehensive thermodynamic characterization of the structural stability and its modulation by the interaction with its zinc (Zn²⁺) cofactor using a combination of experimental and computational techniques. HDAC8 represents an interesting example of an allosteric protein in the broad sense, in which its cofactor, the zinc ion, modulates its conformational equilibrium. The native, inactive, zinc-free state is physiologically relevant considering that the intracellular concentration of zinc is very low and may constitute a valid target for drug discovery.