Bode Wolfram
The Proteinase Research Group, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Semin Thromb Hemost. 2006 Apr;32 Suppl 1:16-31. doi: 10.1055/s-2006-939551.
Through a series of successive, cascade-like proteinase activation and amplification steps, any vascular injury triggers a rapid burst of alpha-thrombin, a trypsin-like serine proteinase. Thrombin, the main executioner of the coagulation cascade, has procoagulant as well as anticoagulant and antifibrinolytic properties. It exhibits quite diverse physiological functions, but also gives rise to several thrombotic disorders, such as thromboembolism, myocardial infarction, and stroke, thus making it an attractive target for antithrombotic agents. Thrombin interacts specifically with several protein substrates, receptors, cofactors, inhibitors, carbohydrates, and modulators. It cleaves fibrinogen, factors XI (FXI) and FXIII, cofactors V and VIII, and the thrombin receptors; uses thrombomodulin to activate protein C and thrombin-activatable-fibrinolysis inhibitor; is inhibited by heparin cofactor II and antithrombin III with the help of acidic carbohydrates; and its activity/specificity is modulated by sodium ions. A large number of crystal structures of alpha-thrombin in complexes with synthetic polypeptides and protein inhibitors, substrate fragments, cofactors, and carbohydrates have displayed extended recognition sites on the thrombin surface, reflecting the versatility and multifunctional specificity of this remarkable proteinase. These structures essentially show that the thrombin surface can be subdivided into several functional regions, which recognize different chemical moieties. By using different combinations of these surface elements, thrombin can interact with a variety of molecules with high specificity, accounting for its multifunctional properties.
通过一系列连续的、级联式的蛋白酶激活和放大步骤，任何血管损伤都会引发α-凝血酶的快速爆发，α-凝血酶是一种类似胰蛋白酶的丝氨酸蛋白酶。凝血酶是凝血级联反应的主要执行者，具有促凝血以及抗凝血和抗纤维蛋白溶解特性。它具有相当多样的生理功能，但也会引发多种血栓性疾病，如血栓栓塞、心肌梗死和中风，因此使其成为抗血栓药物的一个有吸引力的靶点。凝血酶与多种蛋白质底物、受体、辅因子、抑制剂、碳水化合物和调节剂特异性相互作用。它裂解纤维蛋白原、因子XI（FXI）和FXIII、辅因子V和VIII以及凝血酶受体；利用血栓调节蛋白激活蛋白C和凝血酶可激活的纤维蛋白溶解抑制剂；在酸性碳水化合物的帮助下被肝素辅因子II和抗凝血酶III抑制；其活性/特异性受钠离子调节。大量α-凝血酶与合成多肽、蛋白质抑制剂、底物片段、辅因子和碳水化合物形成复合物的晶体结构显示，凝血酶表面存在扩展的识别位点，反映了这种非凡蛋白酶的多功能性和多特异性。这些结构基本上表明，凝血酶表面可细分为几个功能区域，这些区域识别不同的化学基团。通过使用这些表面元件的不同组合，凝血酶可以与多种分子高度特异性地相互作用，这解释了它的多功能特性。
