作为哺乳细胞内丰度最高的枢纽蛋白之一，超大分子机器AAA ATPase p97参与调控蛋白降解、细胞膜融合、细胞生长周期等多个重要生命过程，并与包括癌症、阿兹海默以及帕金森等神经退行性疾病在内的众多人类疾病紧密相关。事实上，作为极有希望攻克上述疾病的药靶蛋白，关于p97的研究长久以来一直是国际上的研究热点之一。然而，由于p97与其底物分子的高度动态的内在结合特性使得相关研究颇为困难，严重阻碍了人们对于其功能机制的认知。本课题将以核磁共振为主要研究工具，对p97与底物蛋白的动态结合机理做深入系统的研究，阐明其相互作用机制，并力图解析出p97在底物转运过程的不同阶段与其底物分子的复合体结构，并据此从原子角度上阐明以ATP为燃料的p97底物分子转运机理。上述工作将帮助我们更好地理解p97蛋白在生命活动中的功能机制，并为药物设计提供重要的理论指导。

The essential and very abundant mammalian protein p97 (also called VCP or Cdc48 in yeast) is an AAA (ATPase associated with a variety of cellular activities) ATPase，which is involved in a variety of important cellular processes including protein degradation, homotypic membrane fusion and cell cycle control. Consequently, the central cellular hub p97 is closely linked to many human diseases, such as cancer and a number of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. Indeed, p97 has been regarded as a very promising therapeutic target in the treatment of these diseases. However, mechanistic understanding of the function of this protein has been greatly hampered by the scarcity of knowledge that how p97 dynamically recognizes and interacts with its client proteins. By marring modern NMR methods with other biophysical and biochemical techniques, this project will focus primarily on the interaction studies of p97 with a few distinct client proteins，aiming to provide structural basis for the universal principles that govern the recognition and dynamic interaction of p97 with its clients. The ultimate goal of this project is to elucidate the mechanism that how the ATP-fueled motor p97 translocates its clients. We believe our efforts should provide a better mechanistic understanding of this critical protein, and thus eventually make significant contributions to.the area of therapeutic design.