title: The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.
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.
authors.affiliation: Max-Planck-Institut für Biochemie, Abt. Strukturforschung, D-82152 Martinsried, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Engel
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Leona
authors.initials: L
authors.lastname: Wagner
authors.forename: Michael
authors.initials: M
authors.lastname: Wermann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heiser
authors.forename: Reiner
authors.initials: R
authors.lastname: Kiefersauer
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.forename: Wolfram
authors.initials: W
authors.lastname: Bode
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Hans
authors.initials: H
authors.lastname: Brandstetter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D018076:DNA, Complementary; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011480:Protease Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013552:Swine
chemical_list: D018076:DNA, Complementary; D011480:Protease Inhibitors; D018819:Dipeptidyl Peptidase 4