Structure of a serpin-protease complex shows inhibition by deformation
Structure of a serpin-protease complex shows inhibition by deformation
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DOI：
10.1038/35038119
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发表时间：
2000-10-19
期刊：
影响因子：
64.8
通讯作者：
Carrell, RW
中科院分区：
文献类型：
--
作者：
Huntington, JA;Read, RJ;Carrell, RW
丝氨酸蛋白酶抑制剂已进化为人类丝氨酸蛋白酶抑制剂的主要家族（1，2）。它们独特的抑制机制涉及构象的深刻变化（3），尽管这种变化的性质和意义一直存在争议。在这里，我们报告了一个典型的丝氨酸蛋白酶蛋白酶复合物的晶体结构，并显示抑制机制。构象变化是由蛋白酶的活性丝氨酸与丝氨酸蛋白酶抑制剂的反应中心反应引发的。这会切割反应中心，然后将其移动71埃到丝氨酸蛋白酶抑制剂的另一极，将拴系的蛋白酶带在一起。两个分子的紧密连接和导致的结构重叠不会影响超稳定的丝氨酸蛋白酶抑制剂，但会导致蛋白酶中37%的结构损失。这是由丝氨酸从其活性位点的拔出以及酶原活化过程中形成的相互作用的破坏引起的（4）。催化位点的破坏防止蛋白酶从复合物中释放，结构紊乱允许其蛋白水解破坏（5，6）。正是构象机制压碎以及抑制蛋白酶的这种能力为丝氨酸蛋白酶抑制剂提供了它们的选择性优势。
The serpins have evolved to be the predominant family of serine-protease inhibitors in man(1,2). Their unique mechanism of inhibition involves a profound change in conformation(3), although the nature and significance of this change has been controversial. Here we report the crystallographic structure of a typical serpin-protease complex and show the mechanism of inhibition. The conformational change is initiated by reaction of the active serine of the protease with the reactive centre of the serpin. This cleaves the reactive centre, which then moves 71 Angstrom to the opposite pole of the serpin, taking the tethered protease with it. The tight linkage of the two molecules and resulting overlap of their structures does not affect the hyperstable serpin, but causes a surprising 37% loss of structure in the protease. This is induced by the plucking of the serine from its active site, together with breakage of interactions formed during zymogen activation(4). The disruption of the catalytic site prevents the release of the protease from the complex, and the structural disorder allows its proteolytic destruction(5,6). It is this ability of the conformational mechanism to crush as well as inhibit proteases that provides the serpins with their selective advantage.