STRUCTURAL STUDIES ON FIBRINOGEN AND FIBRIN

该项目的长期目标仍然是实现原子- 人纤维蛋白原分子的水平结构和 在其转化为纤维蛋白凝块期间发生的相互作用。 为此，我们建议解决几个的X射线结构 人纤维蛋白原的主要片段，从片段D开始，然后 继续到称为D-二聚体的因子XIII交联部分，然后 片段E，复合物“D2 E”，最后，一些小的纤维蛋白原， 其他生物。我们已经收集了来自 片段D的分辨率为3.5 A，并有几个有希望的同晶 重金属衍生物我们目前正在尝试分阶段收集数据 并确定可解释的电子密度图。我们还有水晶 与Gly-Pro-Arg-Pro-酰胺复合的片段D。值得注意的是，这些 与（自由）D处于不同的空间群，并且具有不同的单位 cell.单位细胞是如此之大，我们可能不得不收集数据， 这些晶体在同步加速器设施。我们计划解决 一旦已知（自由）D结构，通过分子置换。我们也 D二聚体晶体在手上所有这些研究应该揭示许多 纤维蛋白原结构的细节以及分子如何在 纤维蛋白形成的早期步骤。遗传学的结构基础 还将阐明缺陷的人纤维蛋白原。我们还计划 继续我们对肽类抗聚合物的长期研究， 根据所确定的结构是可能的。 最后是 是这些结构和其他蛋白质之间的进化联系 (e.g., tenascin），我们计划利用。

The long-term goal of this project remains the attainment of an atomic- level structure of the human fibrinogen molecule and the elucidation of the interactions that occur during its transformation into fibrin clots. To this end, we are proposing to solve the X-ray structures of several major fragments of human fibrinogen, beginning with fragment D, and then continuing on to the factor XIII-crosslinked moiety known as D-dimer, then fragment E, the complex "D2E", and finally, some small fibrinogens from other creatures. We have already collected data from the crystals of fragment D at a resolution of 3.5 A and have several promising isomorphous heavy metal derivatives in hand. We are currently trying to phase the data and determine an interpretable electron density map. We also have crystals of fragment D complexed with Gly-Pro-Arg-Pro-amide. Significantly, these are in a different space group from the (free) D and have a different unit cell. The unit cell is so large that we may have to collect data from these crystals at a synchrotron facility. We plan to solve the structure by molecular replacement once the (free) D structure is known. We also have the D-dimer crystals in hand. All of these studies should reveal many details of fibrinogen structure and how the molecules interact in the early steps of fibrin formation. The structural basis of genetically defective human fibrinogens will also be clarified. We also plan to continue our longstanding study on peptide antipolymerants, better designs being possible in the light of the determined structures. Finally, there are evolutionary connections between these structures and other proteins (e.g., tenascin) that we plan to exploit.