Carrell R W, Evans D L, Stein P E
Department of Haematology, University of Cambridge, MRC Centre, UK.
Nature. 1991 Oct 10;353(6344):576-8. doi: 10.1038/353576a0.
Two protease inhibitors in human plasma play a key part in the control of thrombosis: antithrombin inhibits coagulation and the plasminogen activator inhibitor PAI-1 inhibits fibrinolysis, the dissolving of clots. Both inhibitors are members of the serpin family and both exist in the plasma in latent or inactive forms. We show here that the reactive centre of the serpins can adopt varying conformations and that mobility of the reactive centre is necessary for the function of antithrombin and its binding and activation by heparin; the identification of a new locked conformation explains the latent inactive state of PAI-1. This ability to vary conformation not only allows the modulation of inhibitory activity but also protects the circulating inhibitor against proteolytic attack. Together these findings explain the retention by the serpins of a large and unconstrained reactive centre as compared to the small fixed peptide loop of other families of serine protease inhibitors.
抗凝血酶抑制凝血，而纤溶酶原激活物抑制剂1（PAI - 1）抑制纤维蛋白溶解，即血栓溶解。这两种抑制剂都是丝氨酸蛋白酶抑制剂（serpin）家族的成员，且都以潜在或无活性形式存在于血浆中。我们在此表明，丝氨酸蛋白酶抑制剂的反应中心可呈现不同构象，且反应中心的可移动性对于抗凝血酶的功能及其与肝素的结合和激活是必需的；一种新的锁定构象的鉴定解释了PAI - 1的潜在无活性状态。这种构象变化的能力不仅允许调节抑制活性，还能保护循环中的抑制剂免受蛋白水解攻击。这些发现共同解释了与其他丝氨酸蛋白酶抑制剂家族的小而固定的肽环相比，丝氨酸蛋白酶抑制剂为何保留了一个大且不受约束的反应中心。
