1ORW

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

1ORW の概要

• エントリーDOI: 10.2210/pdb1orw/pdb
• 関連するPDBエントリー: 1ORV
• 分子名称: 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)
• 機能のキーワード: serine protease, oxyanion hole, substrate channeling, drug design, diabetes mellitus, hydrolase
• 由来する生物種: Sus scrofa (pig)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 347128.38

構造登録者

Engel, M.,Hoffmann, T.,Wagner, L.,Wermann, M.,Heiser, U.,Kiefersauer, R.,Huber, R.,Bode, W.,Demuth, H.U.,Brandstetter, H. (登録日: 2003-03-16, 公開日: 2003-05-06, 最終更新日: 2025-03-26)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.84 Å)