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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.
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The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.

机译：二肽基肽酶IV（CD26）的晶体结构揭示了其功能调节和酶促机制。

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摘要

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.
机译：膜结合糖蛋白二肽基肽酶IV（DP IV，CD26）是一种独特的多功能蛋白，可作为受体，结合和蛋白水解分子。我们已经确定了从猪肾脏制备的天然DP IV的序列和1.8 A晶体结构。晶体结构揭示了2-2-2对称四聚体组装，这取决于天然糖基化的β螺旋桨叶片IV。晶体结构表明，DP IV的四聚是调节其与其他组分相互作用的关键机制。每个亚基包含两个结构域，具有开放式维可牢拓扑结构的N端八叶β螺旋桨和C端α/β水解酶域。与结构相关的POP和Tricorn蛋白酶的类比表明，底物通过β-螺旋桨通道进入掩埋的活性位点，而产物则通过单独的侧出口离开活性位点。与活性位点复合的二肽模拟抑制剂揭示了底物识别的关键决定因素，包括区分DP IV为氨基肽酶的Glu-Glu基序和结合并激活有效脯氨酸后裂解所需的P（2）-羰基氧的氧阴离子阱。 。我们讨论了这种药物靶蛋白的主动和非主动定点抑制策略。

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