X-ray structures of DPP-4 that have been published since 2003 give rather detailed information about the structural characteristics of the binding site. Many structurally diverse DPP-4 inhibitors have been discovered and it is not that surprising considering the properties of the binding site:
1. A deep lipophilic pocket combined with several exposed aromatic side chains for achieving high affinity small molecule binding.
2. A significant solvent access that makes it possible to tune the physico-chemical properties of the inhibitors that leads to better pharmacokinetic behavior.
DPP-4 is a 766-amino acid transmembrane glycoprotein that belongs to the prolyloligopeptidase family. It consists of three parts; a cytoplasmic tail, a transmembrane region and an extracellular part. The extracellular part is divided into a catalytic domain and an eight-bladed β-propeller domain. The latter contributes to the inhibitor binding site. The catalytic domain shows an α/β-hydrolase fold and contains the catalytic triad Ser630 - Asp708 - His740. The S1-pocket is very hydrophobic and is composed of the side chains: Tyr631, Val656, Trp662, Tyr666 and Val711. Existing X-ray structures show that there is not much difference in size and shape of the pocket that indicates that the S1-pocket has high specificity for proline residues