ArticleBiochemistry2013
Type II kinase inhibitors show an unexpected inhibition mode against Parkinson's disease-linked LRRK2 mutant G2019S.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Comparative Molecular Dynamics Reveals How LRRK2 Inhibitors Distinguish G2019S from Wild-Type.Neurochemical research · 2025Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade.Genes · 2022Review
- Development of mutation-selective LRRK2 kinase inhibitors as precision medicine for Parkinson's disease and other diseases for which carriers are at increased risk.Frontiers in neurology · 2022Article
- Genetic variations inFrontiers in neurology · 2022Review
- Impact of Type II LRRK2 inhibitors on signaling and mitophagy.The Biochemical journal · 2021Article
- Article
- The structure-function relationship of oncogenic LMTK3.Science advances · 2020Article
- Allosteric inhibition of LRRK2, where are we now.Biochemical Society transactions · 2020Review
- The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition.Experimental neurology · 2018Article
- The dual enzyme LRRK2 hydrolyzes GTP in both its GTPase and kinase domains in vitro.Biochimica et biophysica acta. Proteins and proteomics · 2017Article
- The role of the LRRK2 gene in Parkinsonism.Molecular neurodegeneration · 2014Review
- Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2014Review
- The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.The Journal of biological chemistry · 2014Article
- Structural and functional in silico analysis of LRRK2 missense substitutions.Molecular biology reports · 2014Article
- Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments.Journal of computer-aided molecular design · 2013Article
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6 authors.
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Abstract
A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson's disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the conformational barrier between the active and inactive forms of the enzyme and a relative stabilization of the active form. The conformational bias toward the active form of LRRK2 mutants has two primary consequences. (1) The mutant enzyme becomes hyperactive, a known contributor to the Parkinsonian phenotype, as a consequence of being "locked" into the activated state, and (2) the mutation creates an unusual allosteric pocket that can bind type II inhibitors but in an ATP-competitive fashion. Our results suggest that developing type II inhibitors, which are generally considered superior to type I inhibitors because of desirable selectivity profiles, might be especially challenging for the G2019S LRRK2 mutant.
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