帕金森病是与年龄密切相关的神经退行性疾病之一。LRRK2基因是目前为止突变率最高的帕金森病致病基因，主要表现在LRRK2蛋白激酶活性的异常增高，但其具体生物功能及致病机制仍不明确。深入研究LRRK2蛋白正常生理功能及基因突变的致病机制将为研究帕金森病治疗策略提供分子机制水平的依据。LRRK2蛋白除了具有激酶活性以外，还拥有GTP水解酶活性，该GTP水解酶活性对激酶活性有调节作用，揭示LRRK2蛋白存在分子内调节机制。LRRK2蛋白特有的生化特征使其成为帕金森病非常有希望的治疗靶点。申请者将运用X射线蛋白晶体学，生物化学及生物物理学方法，通过解析LRRK2蛋白中的ROC结构域晶体结构及GTP水解抑制机制来阐明基因突变的致病机理，为新的通过调控GTP水解酶活性来降低LRRK2的激酶活性的方法提供理论依据。

Parkinson’s disease (PD) is a devastating neurological condition that ravages people’s quality of life as it progresses from the subtle loss of muscular coordination, to severe physical and mental disability, to eventual death. There is no cure and no available treatments to stop this disease progression. Today, mutations in LRRK2 are the most prevalent known genetic causes of Parkinson’s disease, for both familial and sporadic cases. In spite of the intensive efforts over the past decade, the molecular role of LRRK2 in disease pathogenesis, its function, and the effects of disease-causing mutations remain unknown. Understanding the underlying mechanism of LRRK2 normal function and how it is affected by the disease-associated mutations will reveal novel mechanism-based therapeutic strategies. In addition to LRRK2 being associated with PD and being the most promising drug target for the disease, LRRK2 is an immensely intriguing protein, in that it has two enzymatic activities (GTPase activity and Kinase activity) that, together with other non-enzymatic domains, potentially represent a unique example of an intramolecular signaling system. The concept of the Roc GTPase domain functioning as a molecular switch regulating the overall activity of LRRK2 is conceptually interesting from a biochemical perspective, and it is the key to LRRK2’s normal function and disease process. In addition to the relatively wide prevalence of LRRK2 in PD, it is the most attractive target for drug discovery, because over-activation of its kinase activity is linked to disease pathogenesis, and it is an enzyme with active sites well suited for binding potential drugs. Indeed, LRRK2 kinase activity was effectively inhibited by broad kinase inhibitors that compete for ATP in the ATP-binding pocket. However, their translation into the clinic has been difficult due to adverse effects. Various potential alternative strategies are being considered, including targeting the Roc domain. This proposed study seeks to define the structures of ROC domain and its mutants to understand the GTP hydrolysis mechanism and mutations pathogenesis by using X-ray diffraction crystallography, protein biochemistry and biophysics approaches, which could provide insight into locations on LRRK2 structures that are suitable for mechanism-based drug discovery.