The crystal structure of dipeptidyl peptidase IV(CD26) reveals its functional regulation and enzymatic mechanism
The crystal structure of dipeptidyl peptidase IV(CD26) reveals its functional regulation and enzymatic mechanism
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DOI：
10.1073/pnas.0230620100
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发表时间：
2003-04-29
影响因子：
11.1
通讯作者：
Brandstetter, H
中科院分区：
文献类型：
--
作者：
Engel, M;Hoffmann, T;Brandstetter, H
膜结合的糖蛋白二肽基肽酶IV（DP IV，CD26）是一种独特的多功能蛋白，充当受体，结合和蛋白水解分子。我们已经确定了由猪肾脏制备的天然DP IV的序列和1.8的晶体结构。晶体结构揭示了一个2-2-2对称四聚体组件，该组件取决于本良糖基化的β-螺旋桨叶片IV。晶体结构表明DP IV的四聚体是调节其与其他组件相互作用的关键机制。每个亚基都包括两个结构域，即带开放魔术贴拓扑的N端八叶β-螺旋桨和C末端alpha/beta-Hydrololase结构域。与结构相关的POP和Tricorn蛋白酶的类比表明，底物通过P螺旋桨隧道访问埋藏的活性位点，而产品通过单独的侧面出口离开活动位置。模仿与活性位点复合的二肽抑制剂公开了底物识别的关键决定因素，包括将DIP IV区分开为氨基肽酶的GLU-GLU基序，以及结合并激活P-2-辅助氧气的氧气陷阱和氧气陷阱。我们讨论该药物靶蛋白的主动和非活动地点定向抑制策略。
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 p-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 DIP 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.