Aertgeerts_2004_Protein.Sci_13_412

Reference

Title : Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation - Aertgeerts_2004_Protein.Sci_13_412
Author(s) : Aertgeerts K , Ye S , Tennant MG , Kraus ML , Rogers J , Sang BC , Skene RJ , Webb DR , Prasad GS
Ref : Protein Science , 13 :412 , 2004
Abstract :

Dipeptidyl peptidase IV (DPPIV) is a member of the prolyl oligopeptidase family of serine proteases. DPPIV removes dipeptides from the N terminus of substrates, including many chemokines, neuropeptides, and peptide hormones. Specific inhibition of DPPIV is being investigated in human trials for the treatment of type II diabetes. To understand better the molecular determinants that underlie enzyme catalysis and substrate specificity, we report the crystal structures of DPPIV in the free form and in complex with the first 10 residues of the physiological substrate, Neuropeptide Y (residues 1-10; tNPY). The crystal structure of the free form of the enzyme reveals two potential channels through which substrates could access the active site-a so-called propeller opening, and side opening. The crystal structure of the DPPIV/tNPY complex suggests that bioactive peptides utilize the side opening unique to DPPIV to access the active site. Other structural features in the active site such as the presence of a Glu motif, a well-defined hydrophobic S1 subsite, and minimal long-range interactions explain the substrate recognition and binding properties of DPPIV. Moreover, in the DPPIV/tNPY complex structure, the peptide is not cleaved but trapped in a tetrahedral intermediate that occurs during catalysis. Conformational changes of S630 and H740 between DPPIV in its free form and in complex with tNPY were observed and contribute to the stabilization of the tetrahedral intermediate. Our results facilitate the design of potent, selective small molecule inhibitors of DPPIV that may yield compounds for the development of novel drugs to treat type II diabetes.

PubMedSearch : Aertgeerts_2004_Protein.Sci_13_412
PubMedID: 14718659
Gene_locus related to this paper: human-DPP4

Related information

Substrate tNPY
Gene_locus tNPY    human-DPP4
Structure tNPY    human-DPP4    1R9M    1R9N

Citations formats

Aertgeerts K, Ye S, Tennant MG, Kraus ML, Rogers J, Sang BC, Skene RJ, Webb DR, Prasad GS (2004)
Crystal structure of human dipeptidyl peptidase IV in complex with a decapeptide reveals details on substrate specificity and tetrahedral intermediate formation
Protein Science 13 :412

Aertgeerts K, Ye S, Tennant MG, Kraus ML, Rogers J, Sang BC, Skene RJ, Webb DR, Prasad GS (2004)
Protein Science 13 :412