Sandbox Reserved 1442

The DPP-IV active site exists at the intersection of a α/β hydrolase domain and a β-propeller domain and consists of the catalytic triad and supporting residues. The catalytic triad is made up of a nucleophile, Serine630, a base, Histidine740, and an acid, Aspartate708. Also essential to the cleaving mechanism are two supporting residues, Tyr547 and Tyr631, that stabilize the oxyanion tetrahedral intermediate by forming hydrogen bonds with the oxyanion. In addition, there are anchoring residues that coordinate the carbonyl of the N-terminal amino acid residue of the substrate and align it for the nucleophilic attack by Ser630. These residues are Glu205, Glu206, Asn710, and Arg125.

Creation of Nucleophile

The hydrogen bond between the carboxyl group of aspartate, which is deprotonated at physiological pH, and histidine increases the pKa of the imidazole nitrogen of histidine from 7 to 12, thus increasing its basicity. It also aligns histidine within the active site by restricting rotation of its side chain.