Figure 1. Catalytic triads of aspartic acid, histidine and serine in four unrelated protease folds. Catalytic residues are shown in black. (a) Clan PA proteases such as trypsin (PDB ID 1OS8) are the most common serine protease in the human genome. (b) Few examples of clan SB proteases are found in the human genome, yet play critical roles in protein processing. The fold is shared with subtilisin (PDB ID 1SCN), an enzyme that has been the subject of intense protein engineering studies. (c) Prolyl oligopeptidase (PDB ID 1QFS) from clan SC is an example of the catalytically diverse /-hydrolase fold. A seven-bladed propeller caps the active site (not shown) of this protease to restrict selectivity of this enzyme towards oligopeptide substrates not longer than 30 amino acids. (d) Several members of clan SK are responsible for intracellular protein levels in bacteria, which lack proteasomes. For example, only one monomer of ClpP (PDB ID 1TYF) is shown of a homooligomer of 14 monomers that combine to yield a large central cavity for polypeptide destruction.

Figure 2. Catalytic mechanism of serine proteases. A strong nucleophile results from the concerted activity of the histidine imidazole and carboxyl group of aspartic acid on a serine hydroxyl group. Residues are labelled according to chymotrypsin numbering. Formation of a tetrahedral intermediate is the key conformational step for both acylation and deacylation. In many serine proteases, an analogous residue to Asp102 plays a diminished or absent role. Many protease families employ a dyad mechanism where creation of the nucleophilic serine results from a pairing with either histidine or lysine. The catalytic mechanism is similar irrespective of dyad or triad chemistry.