Capturing Differences in the Regulation of LRRK2 Dynamics and Conformational States by Small Molecule Kinase Inhibitors.

ABSTRACT: Mutations in the human leucine rich repeat protein kinase-2 (LRRK2) create risk factors for Parkinson's disease, and pathological functions of LRRK2 are often correlated with aberrant kinase activity. Past research has focused on developing selective LRRK2 kinase inhibitors. In this study, we combined enhanced sampling simulations with HDX-MS to characterize the inhibitor-induced dynamic changes and the allosteric communications within the C-terminal domains of LRRK2, LRRK2^RCKW. We find that the binding of MLi-2 (a type I kinase inhibitor) stabilizes a closed kinase conformation and reduces the global dynamics of LRRK2^RCKW, leading to a more compact LRRK2^RCKW structure. In contrast, the binding of Rebastinib (a type II kinase inhibitor) stabilizes an open k

SUBMITTER: Weng JH 

PROVIDER: S-EPMC10127209 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature