X-RAY CRYSTALLOGRAPHY

这个项目的目标是提供详细的原子水平的结构决定因素，影响选择性和有效的抑制半胱氨酸蛋白酶的活性参与寄生虫感染的理解。恰加斯病、非洲昏睡病、疟疾和利什曼病（分别为克氏锥虫、布氏锥虫、恶性疟原虫和几种利什曼原虫）的病原体各自含有对生命周期或生物体至关重要的半胱氨酸蛋白酶。这些蛋白酶已被鉴定和生物化学表征。在与William Bauh的合成化学小组的合作中，这些半胱氨酸蛋白酶的化学，静电和空间拓扑结构将通过与几个系列的小分子合成抑制剂结合的酶的高分辨率X射线晶体结构进行映射。还将研究蛋白酶的大分子内源性抑制剂与酶的复合物，以详细说明识别的扩展模式和变构效应的影响。由于结构信息是过去25年来开发新疗法的众多进展的基础，因此从小和大分子复合物结构获得的见解将用作抑制剂合理设计的下一个周期的起点。这项工作将与联合国人权事务高级专员小组以及联合国人权事务高级专员办事处合作进行。 Fred Cohen/Andrej Sali计算核心。

The goal of this project is to provide detailed atomic-level understanding of the structural determinants that affect selective and potent inhibition of the activity of cysteine protease involved in parasitic infection. The causative agents of Chagas' disease, African sleeping sickness, malaria and leishmaniasis (Trypanosoma cruzi, Trypanosoma brucei, Plasmodium falciparum and several Leishmania species, respectively) each contain cysteine proteases that are critical to the life cycles or the organisms. These proteases have been identified and biochemically characterized. In collaboration with William Roush's synthetic chemistry group, the chemical, electrostatic and steric topology of these cysteine proteases will be mapped via high resolution X-ray crystallographic structures of the enzymes bound to several series of small molecule synthetic inhibitor. Macromolecular endogenous inhibitors of the proteases will also be studied in complex with the enzymes in order to detail extended modes of recognition and the impact of allosteric effects. As structural information has been the basis for numerous advances in the development of new therapeutics in the last 25 years, insights obtained from both small and macromolecular complex structures will be used as starting points for next cycles of rational design of inhibitors. This work will be done in collaboration with the Roush group as well as the Fred Cohen/Andrej Sali computational cores.