Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations
Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations
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DOI：
10.1073/pnas.1203223109
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发表时间：
2012-06-26
影响因子：
11.1
通讯作者：
Kortholt, Arjan
中科院分区：
文献类型：
--
作者：
Gilsbach, Bernd K.;Ho, Franz Y.;Kortholt, Arjan
人类富含亮氨酸重复蛋白激酶2(LRRK2)的突变已被发现是迟发性帕金森病最常见的原因。在这里，我们证明盘状网柄菌是研究LRRK2激酶结构和生化特性的合适模型，并可用于电流的优化和新的LRRK2抑制剂的鉴定。我们已经解决了野生型帕金森病相关突变体G1179S和L1180T(LRRK2中的G2019S和I2020T)的结构以及Roco4激酶与LRRK2抑制剂H1152的复合体的结构。综上所述，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。
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.