Structural basis of compound recognition by adenosine deaminase
Structural basis of compound recognition by adenosine deaminase
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DOI：
10.1021/bi050529e
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发表时间：
2005-08-09
期刊：
影响因子：
2.9
通讯作者：
Fujii, T
中科院分区：
文献类型：
--
作者：
Kinoshita, T;Nakanishi, I;Fujii, T
对应于各种状态的结构快照能够阐明酶的分子识别机制。腺苷脱氨酶有两种不同的构象，一种是开放型，一种是封闭型，尽管目前还不清楚是什么因素影响了替代构象的适应性。在这里，我们确定了第一个非连接结构作为初始状态，这是开放的形式，从而合理地推导出分子识别机制。在非连接和连接状态下的活性位点的检查表明，在非连接状态下的水结合位置之一的占用率在确定交替构象中是非常重要的。当该位置为空时，Phe 65随后朝向空间的移动引起闭合形式。另一方面，当被占据时，整体构象保持开放形式。这种结构上的理解将极大地有助于结构导向的药物设计，并能够控制酶的活性。
Structural snapshots corresponding to various states enable elucidation of the molecular recognition mechanism of enzymes. Adenosine deaminase has two distinct conformations, an open form and a closed form, although it has so far been unclear what factors influence adaptation of the alternative conformations. Herein, we have determined the first nonligated structure as an initial state, which was the open form, and have thereby rationally deduced the molecular recognition mechanism. Inspection of the active site in the nonligated and ligated states indicated that occupancy at one of the water-binding positions in the nonligated state was highly significant in determining alternate conformations. When this position is empty, subsequent movement of Phe65 toward the space induces the closed form. On the other hand, while occupied, the overall conformation remains in the open form. This structural understanding should greatly assist structure-oriented drug design and enable control of the enzymatic activity.