Chinnaraj Mathivanan, Planer William, Pozzi Nicola
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States.
Front Med (Lausanne). 2018 Oct 2;5:281. doi: 10.3389/fmed.2018.00281. eCollection 2018.
Coagulation factor II, or prothrombin, is a multi-domain glycoprotein that is essential for life and a key target of anticoagulant therapy. In plasma, prothrombin circulates in two forms at equilibrium, "closed" (80%) and "open" (20%), brokered by the flexibility of the linker regions. Its structure remained elusive until recently when our laboratory solved the first X-ray crystal structure of the zymogen locked in the predominant closed form. Because of this technical breakthrough, fascinating aspects of the biology of prothrombin have started to become apparent, and with this, novel and important questions arise. Here, we examine the significance of the "closed"/"open" equilibrium in the context of the mechanism of thrombin generation. Further, we discuss the potential translational opportunities for the development of next-generation anticoagulants that arise from this discovery. By providing a structural overview of each alternative conformation, this minireview also offers a relevant example of modern structural biology and establishes a practical workflow to elucidate the structural features of analogous clotting and complement factors.
凝血因子II，即凝血酶原，是一种多结构域糖蛋白，对生命至关重要，也是抗凝治疗的关键靶点。在血浆中，凝血酶原以两种形式处于平衡状态循环，即“闭合”形式（约80%）和“开放”形式（约20%），这两种形式由连接区的灵活性调节。直到最近我们实验室解析了以主要闭合形式锁定的酶原的首个X射线晶体结构，其结构才得以明确。由于这一技术突破，凝血酶原生物学中引人入胜的方面开始变得清晰，随之而来的是新的重要问题。在此，我们在凝血酶生成机制的背景下探讨“闭合”/“开放”平衡的意义。此外，我们讨论了这一发现为下一代抗凝剂开发带来的潜在转化机会。通过提供每种替代构象的结构概述，本综述还提供了现代结构生物学的一个相关实例，并建立了阐明类似凝血因子和补体因子结构特征的实用工作流程。
