U.S.-Japan Cooperative Science: The Interrelationship of Protein Flexibility, Activity and Thermal Stability

9815759 Petsko该奖项支持Brandeis大学的Gregory Petsko教授和日本东京药学与生命科学大学的Tairo Oshima教授之间为期三年的合作研究项目。研究人员将对蛋白质弹性、活性和热稳定性之间的相互关系进行研究。蛋白质是高度灵活的分子，但这种灵活性在其生物活性和结构稳定性中的作用(如果有的话)仍然是一个悬而未决的问题。蛋白质的工业和医疗用途需要在广泛的温度范围内保持活性的分子，但控制高温稳定性的规则还没有被很好地理解。这项合作的目的是确定蛋白质灵活性、催化活性和热稳定性之间的相互关系。所使用的模型系统是来自几种生物(嗜热嗜热菌、大肠杆菌、鼠伤寒沙门氏菌和弧菌15)的3-异丙基苹果酸脱氢酶。为了提供与这些性质相关的数据，设计了一系列实验，结合了遗传选择、X射线结晶学、动力学分析以及通过分析B因子绘制蛋白质柔性图。该项目汇集了两个拥有互补专业知识和研究能力的实验室的努力。这项研究的结果应该揭示描述酶的动态行为如何有助于催化效率以及蛋白质结构的灵活性如何影响蛋白质展开的温度的基本原理。根据这些原理，应该有可能在不削弱中温(人类)蛋白质活性的情况下，设计出温度稳定性更好的中温(人类)蛋白质。这项研究通过研究生的参与促进了国际人力资源的发展。通过思想和技术的交流，这个项目将扩大我们的基础知识基础，促进国际理解与合作。***

9815759PetskoThis award supports a three year collaborative research project between Professor Gregory Petsko of Brandeis University and Professor Tairo Oshima of the Tokyo University of Pharmacy and Life Science in Japan. The researchers will be undertaking a study of the interrelationship of protein flexibility, activity and thermal stability. Proteins are highly flexible molecules, but the role, if any, of this flexibility in their biological activity and structural stability is still an open question. Industrial and medical uses of proteins require molecules that retain activity over a wide range of temperatures, but the rules governing stability at high temperatures are not well understood. The aim of this collaboration is to determine the interrelationship between protein flexibility, catalytic activity and thermal stability. The model system to be used is 3-isopropylmalate dehydrogenase from several organisms (Thermus thermophilus, Escherichia coli, Samonella typhimurium, and Vibrio sp.15). A series of experiments combining genetic selection, X-ray crystallography, kinetic analysis and the mapping of protein flexibility by the analysis of B-factors have been designed to provide data relating these properties. This project brings together the efforts of two laboratories that have complementary expertise and research capabilities. Results of this research should reveal the basic principles that describe how the dynamic behavior of an enzyme contributes to catalytic efficiency and how flexibility in a protein structure affects the temperature at which that protein unfolds. From these principles it should be possible to design improved temperature stability into mesophilic (human) proteins without crippling their activity. This research advances international human resources through the participation of graduate students. Through the exchange of ideas and technology, this project will broaden our base of basic knowledge and promote international understanding and cooperation. ***