1ORW

Crystal Structure of Porcine Dipeptidyl Peptidase IV (CD26) in Complex with a Peptidomimetic Inhibitor

Summary for 1ORW

• Entry DOI: 10.2210/pdb1orw/pdb
• Related: 1ORV
• Descriptor: dipeptidyl peptidase IV, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: serine protease, oxyanion hole, substrate channeling, drug design, diabetes mellitus, hydrolase
• Biological source: Sus scrofa (pig)
• Total number of polymer chains: 4
• Total formula weight: 347128.38

Authors

Engel, M.,Hoffmann, T.,Wagner, L.,Wermann, M.,Heiser, U.,Kiefersauer, R.,Huber, R.,Bode, W.,Demuth, H.U.,Brandstetter, H. (deposition date: 2003-03-16, release date: 2003-05-06, Last modification date: 2025-03-26)

Primary citation

Engel, M.,Hoffmann, T.,Wagner, L.,Wermann, M.,Heiser, U.,Kiefersauer, R.,Huber, R.,Bode, W.,Demuth, H.U.,Brandstetter, H.
The Crystal Structure of Dipeptidyl Peptidase IV (CD26) Reveals its Functional Regulation and Enzymatic Mechanism
Proc.Natl.Acad.Sci.USA, 100:5063-5068, 2003

PubMed 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.

PubMed: 12690074
DOI: 10.1073/pnas.0230620100

Experimental method

X-RAY DIFFRACTION (2.84 Å)