Dipeptidyl peptidase IV (DPP-IV, also known as CD26), a multifunctional transmembrane serine protease, has been attracting considerable interest in recent years as a potential target for type 2 diabetes, owing to its role in regulating blood sugar, and initial trials of DPP-IV inhibitors in humans have been promising. The structure of DPP-IV in complex with an inhibitor, reported in the January issue of Nature Structural Biology, indicates how substrate specificity is achieved, and should be valuable in understanding the structure–activity relationships of known and future inhibitors, and in achieving high specificity for DPP-IV over other members of the same protein family.

DPP-IV modulates the activity of several neuropeptides, chemokines and peptide hormones by specifically cleaving Xaa-Pro or Xaa-Ala from their amino termini. Cleavage of glucagon-like peptide and glucose-dependent insulinotropic peptide — which together are largely responsible for stimulating insulin secretion by β-cells in response to food — terminates their action. By delaying this normally rapid degradation, DPP-IV inhibitors combat the defects in the effects or production of insulin present in type 2 diabetes. And because the ability of DPP-IV inhibitors to promote insulin release is strongly glucose dependent, the risk of hypoglycaemia, a serious side effect of current therapies, is reduced.

Biochemical evidence indicates that DPP-IV functions as a dimer, and indeed, in the crystal structure of the extracellular part of DPP-IV in complex with the inhibitor valine-pyrrolidide determined by Rasmussen et al., DPP-IV is a dimer. Each monomeric subunit has an α/β hydrolase domain and an eight-bladed β-propeller domain, and both domains participate in inhibitor binding in the active site, as well as in dimerization. Intriguingly, it seems that part of the β-propeller domain involved in dimerization could act as a 'lid' to the active site if the dimer dissociates, which would provide a structural explanation for the biochemical observations that DPP-IV acts as a dimer, and which could represent a novel opportunity for structure-based drug design to block dimer formation.