3.2.1. Overall structure of zinc-dependent
The HDACs structure is characterized by having an α/β fold topology (Hentchel & Escalante-Semerena, 2015; Yang & Seto, 2008). In some family members, the crystallography analysis shows that one or two domains form the tertiary structure. For example, in the LpxC proteins, the two domains have an identical topology of secondary structural elements that includes a five-stranded parallel β-sheet and two principal α-helices connected by a 16-residue linker (Whittington et al., 2003). In contrast, the HDAC8 comprises a single domain consisting of an eight-stranded parallel β-sheet sandwiched between 13 α-helices (Figure 2C) (Somoza et al., 2004). Interestingly, the crystal structure of PA3774 from the human pathogen P. aeruginosa shares a high degree of homology with class IIb HDACs and consists of two dimers that are close to each other, forming a tetramer, which may be essential for substrate recognition and selectivity (Krämer et al., 2016). Despite these differences, the structural comparison shows that the structural difference is mainly restricted to the loop regions.
The catalytic center contains a zinc ion commonly pentacoordinate by two aspartic acids, a histidine, and a water molecule. In addition to the zinc ligands, two histidine, two aspartic acids, and one tyrosine are also present, which form hydrogen bonds with bound ligands. Single mutations of these residues abolish entirely the activity (Krämer et al., 2016). Furthermore, the surface of this site reveals the formation of a narrow pocket that probably serves to accommodate the acetylated lysine during the catalytic reaction (Vannini et al., 2004). The reaction requires that a conserved histidine residue act as a general base to activate a metal-bound water that attacks the carbonyl of the acetyl group (Figure 2C) (Finnin et al., 1999; Finnin, 2005; Hernick & Fierke, 2006).