丝氨酸蛋白酶抑制剂：自然界的分子捕鼠器。
The serpins: nature's molecular mousetraps.
作者信息
Huntington J A, Carrell R W
机构信息
University of Cambridge, Department of Haematology, Wellcome Trust Centre for Molecular Mechanisms in Disease, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK.
出版信息
Sci Prog. 2001;84(Pt 2):125-36. doi: 10.3184/003685001783239032.
Abstract
A special family of inhibitors, known as the serpins, has evolved an extraordinary mechanism to enable the control of the proteolytic pathways essential to life. The serpins undergo a profound change in conformation to entrap their target protease in an irreversible complex. The solving of the structure of this complex now completes a video depiction of the changes involved. The serpin, just like a mousetrap, is seen to change with a spring-like movement from an initial metastable state to a final hyperstable form. The structure shows how this conformational shift not only inhibits the protease but also destroys it. A bonus from these structural insights is the realisation that a number of diseases, as diverse as thrombosis, cirrhosis and dementia, all share a common mechanism arising from similar mutations of different serpins.
摘要
一类特殊的抑制剂家族，即丝氨酸蛋白酶抑制剂（serpins），已经进化出一种非凡的机制来控制对生命至关重要的蛋白水解途径。丝氨酸蛋白酶抑制剂会经历构象的深刻变化，将其靶蛋白酶捕获在不可逆的复合物中。该复合物结构的解析现在完成了对所涉及变化的动态描述。丝氨酸蛋白酶抑制剂就像一个捕鼠器，被观察到以类似弹簧的运动从初始的亚稳态转变为最终的超稳态形式。该结构展示了这种构象转变不仅如何抑制蛋白酶，还如何将其破坏。这些结构见解带来的额外收获是认识到许多疾病，如血栓形成、肝硬化和痴呆症，都有一个共同的机制，该机制源于不同丝氨酸蛋白酶抑制剂的类似突变。
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本文引用的文献
1
Electrophoretic and immunologic classification of M-components in serum.血清中M成分的电泳和免疫分类
Scand J Clin Lab Invest. 1963;15 Suppl 69:11-24.
2
The serpin inhibitory mechanism is critically dependent on the length of the reactive center loop.
J Biol Chem. 2001 Jul 20;276(29):27541-7. doi: 10.1074/jbc.M102594200. Epub 2001 Apr 26.
3
A serpin-induced extensive proteolytic susceptibility of urokinase-type plasminogen activator implicates distortion of the proteinase substrate-binding pocket and oxyanion hole in the serpin inhibitory mechanism.丝氨酸蛋白酶抑制剂诱导尿激酶型纤溶酶原激活剂产生广泛的蛋白水解敏感性，这表明在丝氨酸蛋白酶抑制剂的抑制机制中，蛋白酶底物结合口袋和氧阴离子洞发生了扭曲。
Eur J Biochem. 2001 Feb;268(3):673-85. doi: 10.1046/j.1432-1327.2001.01921.x.
4
Structure of a serpin-protease complex shows inhibition by deformation.丝氨酸蛋白酶抑制剂-蛋白酶复合物的结构显示通过变形实现抑制作用。
Nature. 2000 Oct 19;407(6806):923-6. doi: 10.1038/35038119.
5
What can the structures of enzyme-inhibitor complexes tell us about the structures of enzyme substrate complexes?酶-抑制剂复合物的结构能让我们了解到关于酶-底物复合物结构的哪些信息？
Biochim Biophys Acta. 2000 Mar 7;1477(1-2):324-37. doi: 10.1016/s0167-4838(99)00284-8.
6
Familial dementia caused by polymerization of mutant neuroserpin.由突变神经丝氨酸蛋白酶聚合引起的家族性痴呆。
Nature. 1999 Sep 23;401(6751):376-9. doi: 10.1038/43894.
7
Formation of the covalent serpin-proteinase complex involves translocation of the proteinase by more than 70 A and full insertion of the reactive center loop into beta-sheet A.共价丝氨酸蛋白酶抑制剂-蛋白酶复合物的形成涉及蛋白酶移位超过70埃以及反应中心环完全插入Aβ折叠。
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8
Genetics and respiratory disease. 2. Alpha 1-antitrypsin deficiency, cirrhosis and emphysema.遗传学与呼吸系统疾病。2. α1抗胰蛋白酶缺乏症、肝硬化和肺气肿。
Thorax. 1998 Jun;53(6):501-5. doi: 10.1136/thx.53.6.501.
9
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Biochemistry. 1996 Aug 20;35(33):10608-15. doi: 10.1021/bi9605806.
10
The serpin superfamily of proteinase inhibitors: structure, function, and regulation.蛋白酶抑制剂的丝氨酸蛋白酶抑制剂超家族：结构、功能与调控
J Biol Chem. 1994 Jun 10;269(23):15957-60.
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