Structural Studies on Fibrinogen and Fibrin

描述（申请人提供）：血凝块的网状结构由 由纤维蛋白原分子系统组装而成的纤维蛋白纤维 被凝血酶水解的蛋白质。在此过程中， 聚合物通过因子XIII-催化引入 各种赖氨酸和谷氨酰胺侧链之间的交联。最终 血凝块被纤溶酶消化。凝血和溶解的一般性质 几十年来，这一过程一直受到赞赏，但详细了解 事件是不可能的，因为三维结构的开始， 纤维蛋白原单位不能在原子水平上测定。所有这些都 在过去三年中，由于一系列高分辨率 纤维蛋白原片段的晶体结构和低分辨率的结构， 天然纤维蛋白原。这些结构非常具有启发性， 一个完整的理解似乎不再遥远。这一行动的直接目标是 项目是获得天然纤维蛋白原的高分辨率晶体结构 通过X射线衍射，首先是一个鸡的结构， 然后是更令人生畏的人类分子，我们只有的晶体 最近观察到的，对于有用的研究来说仍然太小。我们也 建议单独解决结构的一个难以捉摸的，但关键的一部分， 纤维蛋白原是非常移动的，并没有屈服于其他方法。 该提案还描述了确定几个复杂的计划， 分离自交联纤维蛋白，包括称为“D2 E”的部分。“合并 在高分辨率下的天然分子的完整结构，这些 结果应该消除纤维蛋白形成的许多神秘。

Description (provided by applicant): The meshwork of a blood clot is composed of fibrin fibers built up by the systematic assembly of fibrinogen molecules that have been proteolyzed by thrombin. During the process, the resulting polymers are further reinforced by the factor XIII-catalyzed introduction of crosslinks between various lysine and glutamine sidechains. Ultimately, the clot is digested by plasmin. The general nature of the clotting and lysis process has been appreciated for several decades, but a detailed knowledge of events was not possible because the three-dimensional structure of the starting fibrinogen units could not be determined at the atomic level. All this has changed during the past three years as a result of a series of high resolution crystal structures of fibrinogen fragments and a low resolution structure of a native fibrinogen. The structures have been very revealing and the possibility of a full understanding no longer seems remote. The immediate goals of this project are to obtain high-resolution crystal structures of native fibrinogens by X-ray diffraction, first of a chicken structure which is already well under way, and then the more daunting human molecule, crystals of which we have only recently observed and which are still too small for useful study. We also propose to solve separately the structure of an elusive but key part of fibrinogen that is very mobile and which has not yielded to other approaches. The proposal also describes plans for determining several complexes that can be isolated from crosslinked fibrin, including a moiety called "D2E." Combined with the full structures of the native molecules at high resolution, these results should dispel much of the mystery of fibrin formation.