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的了解，这些决定因素影响对寄生虫感染中涉及的半胱氨酸蛋白酶活性的选择性和有效抑制。查加斯病、非洲昏睡病、疟疾和利什曼病(分别是克氏锥虫、布氏锥虫、恶性疟原虫和几种利什曼原虫)的病原体都含有对生命周期或生物体至关重要的半胱氨酸蛋白酶。这些蛋白水解酶已被鉴定，并具有生化特征。在与William Roush的合成化学小组的合作下，这些半胱氨酸蛋白酶的化学、静电和空间拓扑将通过与几系列小分子合成抑制剂结合的酶的高分辨率X射线晶体结构来绘制。还将研究大分子内源性蛋白酶抑制剂与酶的复合体，以详细说明扩展的识别模式和变构效应的影响。在过去的25年里，结构信息一直是新疗法发展的许多进展的基础，从小分子和大分子复杂结构中获得的见解将被用作下一轮合理设计抑制剂的起点。这项工作将与Roush小组以及 弗雷德·科恩/安德烈·萨利计算核心。

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.