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).