Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog

Abstract

Dipeptidyl peptidase IV (DPP-IV/CD26) is a multifunctional type II transmembrane serine peptidase. This enzyme contributes to the regulation of various physiological processes, including blood sugar homeostasis, by cleaving peptide hormones, chemokines and neuropeptides. We have determined the 2.5 A structure of the extracellular region of DPP-IV in complex with the inhibitor valine-pyrrolidide. The catalytic site is located in a large cavity formed between the alpha/beta-hydrolase domain and an eight-bladed beta-propeller domain. Both domains participate in inhibitor binding. The structure indicates how substrate specificity is achieved and reveals a new and unexpected opening to the active site.

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…Biochemical examination reveals that similar to other members of the DPP family [6][7][8][9][10][11]42], DPP9-l also forms dimers and is active, with comparable cleavage characteristics to the shorter DPP9 variant. taken together, these results show for the first time that the endogenous pool of DPP9 protein in cells is composed of at least two different versions: DPP9-S and DPP9-l, which share similar biochemical properties.…”

“…Four active members of this family are known so far: the two membrane-bound cell-surface members dipeptidyl peptidase IV (DPPIV) and the Fibroblast activation protein alpha (FaP), as well as the two soluble members DPP8 and 1 3 DPP9 (reviewed in [3][4][5][6]). Dimerization is a common feature for members of the S9B/DPPIV family [6][7][8][9][10][11] and is essential for enzymatic activity [12][13][14][15][16].…”

Solvent and thermal stability, and pH kinetics, of proline-specific dipeptidyl peptidase IV-like enzyme from bovine serum

“…The active form of human DPP IV is a dimer; the monomer is inactive [24,26,27]. Assuming that the present bovine serum DPP IV-like peptidase also exists as a dimer, the biphasic loss of activity at 71°C may proceed via (i) formation of a partially-unfolded, but still catalytically active, dimeric intermediate and (ii) subsequent dissociation of the dimeric intermediate to inactive monomers.…”

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

“…Subsequently, we used a motif derived from a DPP4 protein 25 , in addition to the trypsin motif used previously 22 , to query a comprehensive and non-redundant (50% sequence identity) list of ~5000 human proteins with known structures using CLASP, intending to identify other proteins that might be inhibited by the gliptins. From the set of proteins with significant congruent matches with these two motifs, we identified a pancreatic lipase 26 and a gastric lipase 27 , keeping the context of lipases, acute pancreatitis and GLP-1 based therapies in mind.…”