Dipeptidyl-peptidases III (DPPIII; EC 126.96.36.199) are Zn-dependent enzymes with molecular masses of ca. 80-85 kDa that specifically cleave the first two amino acids from the N-terminus of different length peptides. All known DPPIII sequences contain the unique motif HEXXGH, which enabled the recognition of the dipeptidyl-peptidase III family as a distinct evolutionary metallopeptidase family (M49). In mammals, DPPIII is associated with important physiological functions such as pain regulation, and hence the enzyme is a potential drug target. Previously, Sigrid Deller and Nina Jajcanin-Jozic have successfully expressed, purified and characterized the recombinant yeast enzyme, and Pravas Baral in Karl Gruber’s laboratory at the Karl-Franzens-University has elucidated the crystal structure of the yeast protein. This work revealed that yeast DPPIII features a novel protein topology.
Structure of human DPPIII in its open form (right) and peptide liganded (closed) form
In collaboration with a structural genomics group in Toronto led by Dr. Sirano Dhe-Paganon, Gustavo Arruda (PhD student in Karl Gruber’s group) solved the structure of the human enzyme both in its open (right, above) and closed conformation (left, above). The latter structure was obtained by co-crystallization of an inactive variant of human DPPIII with a tightly bound peptide. These two new structures constitute a major breakthrough in our effort to understand the physiological role of the enzyme and pave the way for the development of 9 potentially useful inhibitors of the enzyme (this project is supported by Alexandra Binter in our group).