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Dipeptidyl peptidase IV (DPP-IV) is of intense interest as a drug target in diabetes and DPP-IV inhibitors have shown excellent results in clinical trials. The serine peptidase DPP-IV (CD26, EC 3.4.14.5) modulates the biological activity of several peptide hormones, chemokines and neuropeptides by specifically cleaving after a proline or alanine at amino acid position 2 from the N-terminus. DPP-IV hereby contributes to the regulation of processes, such as inflammation and blood glucose homeostasis in particular. This large transmembrane glycoprotein has resisted X-ray diffraction analysis for many years. This paper reports the three-dimensional structure of DDP-IV determined by X-ray crystallography. The three-dimensional structure revealed new and surprising features and the generated knowledge allows new interpretation of earlier reported biochemical data, resulting in a new and improved understanding of the many biological functions reported for DPP-IV.

The knowledge of the three-dimensional crystal structure of DPP-IV is new to the scientific community and it provides both academics and commercial industries with an important tool for designing new DPP-IV inhibitors (potential drug compounds) as well as to understanding the selectivity for peptide substrates.

Dipeptidyl peptidase IV (DPP-IV) is an enzyme widely distributed in the human body. DPP-IV’s function is to cleave smaller peptides. You might say that DPP-IV is a scissor and the peptide is the string being cut. One of the peptides DPP-IV can cleave is called Glucagon-like peptide 1 (GLP-1). GLP-1 stimulates the secretion of insulin in the body. Secretion of insulin is insufficient when a person suffers from type II diabetes.

One way to treat type II diabetes is by injection of the peptide GLP-1. Another way is to rescue the GLP-1 which is naturally present in the body by preventing DPP-IV from cleaving GLP-1.

This rescue can take place if the DPP-IV scissor is blocked. The blockage can be achieved by placing a small drug molecule in the place where DPP-IV is to cut the string. By determining the three-dimensional structure of DPP-IV we have got a perfect picture of the scissor and are able to design the drug molecule to exactly match the scissor in size and shape. The development of the drug compound can now be done in a much more rational fashion and the drug can be achieved faster, much to the benefit of diabetes patients.