Department of Cell Biochemistry, University of Groningen, 9747 AG, Groningen, The Netherlands.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10322-7. doi: 10.1073/pnas.1203223109. Epub 2012 Jun 11.
Mutations in human leucine-rich-repeat kinase 2 (LRRK2) have been found to be the most frequent cause of late-onset Parkinson disease. Here we show that Dictyostelium discoideum Roco4 is a suitable model to study the structural and biochemical characteristics of the LRRK2 kinase and can be used for optimization of current and identification of new LRRK2 inhibitors. We have solved the structure of Roco4 kinase wild-type, Parkinson disease-related mutants G1179S and L1180T (G2019S and I2020T in LRRK2) and the structure of Roco4 kinase in complex with the LRRK2 inhibitor H1152. Taken together, our data give important insight in the LRRK2 activation mechanism and, most importantly, explain the G2019S-related increase in LRRK2 kinase activity.
人类富含亮氨酸重复激酶 2（LRRK2）突变被发现是导致晚发性帕金森病的最常见原因。在这里，我们表明，粘菌 discoideum Roco4 是研究 LRRK2 激酶的结构和生化特性的合适模型，可用于优化现有抑制剂和鉴定新的 LRRK2 抑制剂。我们已经解决了 Roco4 激酶野生型、帕金森病相关突变 G1179S 和 L1180T（LRRK2 中的 G2019S 和 I2020T）以及 Roco4 激酶与 LRRK2 抑制剂 H1152 复合物的结构。总之，我们的数据为 LRRK2 激活机制提供了重要的见解，最重要的是，解释了 G2019S 相关的 LRRK2 激酶活性增加。
