Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations.

Abstract

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.

DOI: 10.1073/pnas.1203223109
050100201220132014201520162017
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@article{Gilsbach2012RocoKS, title={Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations.}, author={Bernd K. Gilsbach and Franz Y F Ho and Ingrid R. Vetter and Peter J. M. Van Haastert and Alfred Wittinghofer and Arjan Kortholt}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2012}, volume={109 26}, pages={10322-7} }