Engel_2003_Proc.Natl.Acad.Sci.U.S.A_100_5063

Reference

Title : The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism - Engel_2003_Proc.Natl.Acad.Sci.U.S.A_100_5063
Author(s) : Engel M , Hoffmann T , Wagner L , Wermann M , Heiser U , Kiefersauer R , Huber R , Bode W , Demuth HU , Brandstetter H
Ref : Proc Natl Acad Sci U S A , 100 :5063 , 2003
Abstract :

The membrane-bound glycoprotein dipeptidyl peptidase IV (DP IV, CD26) is a unique multifunctional protein, acting as receptor, binding and proteolytic molecule. We have determined the sequence and 1.8 A crystal structure of native DP IV prepared from porcine kidney. The crystal structure reveals a 2-2-2 symmetric tetrameric assembly which depends on the natively glycosylated beta-propeller blade IV. The crystal structure indicates that tetramerization of DP IV is a key mechanism to regulate its interaction with other components. Each subunit comprises two structural domains, the N-terminal eight-bladed beta-propeller with open Velcro topology and the C-terminal alpha/beta-hydrolase domain. Analogy with the structurally related POP and tricorn protease suggests that substrates access the buried active site through the beta-propeller tunnel while products leave the active site through a separate side exit. A dipeptide mimicking inhibitor complexed to the active site discloses key determinants for substrate recognition, including a Glu-Glu motif that distinguishes DP IV as an aminopeptidase and an oxyanion trap that binds and activates the P(2)-carbonyl oxygen necessary for efficient postproline cleavage. We discuss active and nonactive site-directed inhibition strategies of this pharmaceutical target protein.

PubMedSearch : Engel_2003_Proc.Natl.Acad.Sci.U.S.A_100_5063
PubMedID: 12690074
Gene_locus related to this paper: pig-dpp4

Related information

Inhibitor p-Iodo-Phe-Pyr-CN
Gene_locus p-Iodo-Phe-Pyr-CN    pig-dpp4
Family p-Iodo-Phe-Pyr-CN    pig-dpp4    DPP4N_Peptidase_S9
Structure p-Iodo-Phe-Pyr-CN    pig-dpp4    DPP4N_Peptidase_S9    1ORV    1ORW

Citations formats

Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth HU, Brandstetter H (2003)
The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism
Proc Natl Acad Sci U S A 100 :5063

Engel M, Hoffmann T, Wagner L, Wermann M, Heiser U, Kiefersauer R, Huber R, Bode W, Demuth HU, Brandstetter H (2003)
Proc Natl Acad Sci U S A 100 :5063