ArticleProceedings of the National Academy of Sciences of the United States of America2019
Crystal structure of the WD40 domain dimer of LRRK2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 98 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Genome-wide association and population-tailored polygenic risk for Parkinson's disease in Taiwan.NPJ Parkinson's disease · 2026Article
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Article
- Cache: Utilizing ultra-large library screening in Rosetta to identify novel binders of the WD-repeat domain of Leucine-Rich Repeat Kinase 2.Journal of cheminformatics · 2025Article
- 14-3-3 binding maintains the Parkinson's associated kinase LRRK2 in an inactive state.Nature communications · 2025Article
- Structural biology of Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2).The Journal of biological chemistry · 2025Review
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Active Learning-Guided Hit Optimization for the Leucine-Rich Repeat Kinase 2 WDR Domain Based on In Silico Ligand-Binding Affinities.Journal of chemical information and modeling · 2025Article
- Virtual screening: hope, hype, and the fine line in between.Expert opinion on drug discovery · 2025Review
- Roles of LRRK2 and its orthologs in protecting against neurodegeneration and neurodevelopmental defects.Frontiers in cell and developmental biology · 2025Article
- The design and development of LRRK2 inhibitors as novel therapeutics for Parkinson's disease.Future medicinal chemistry · 2025Review
- CACHE Challenge #1: Docking with GNINA Is All You Need.Journal of chemical information and modeling · 2024Article
- Molecular dynamics studies reveal the structural impacts of LRRK2 R1441C and LRRK2 D1994A mutations in Parkinson's disease.Biochemistry and biophysics reports · 2024Article
- Mass spectrometry-based proteomics for biomarker discovery in theNeuroprotection (Chichester, England) · 2024Review
- In silico fragment-based discovery of CIB1-directed anti-tumor agents by FRASE-bot.Nature communications · 2024Article
- A designed ankyrin-repeat protein that targets Parkinson's disease-associated LRRK2.The Journal of biological chemistry · 2024Article
- Article
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8 authors at 4 institutions in 2 countries.
Funding
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein with both a Ras of complex (ROC) domain and a kinase domain (KD) and, therefore, exhibits both GTPase and kinase activities. Human genetics studies have linked LRRK2 as a major genetic contributor to familial and sporadic Parkinson's disease (PD), a neurodegenerative movement disorder that inflicts millions worldwide. The C-terminal region of LRRK2 is a Trp-Asp-40 (WD40) domain with poorly defined biological functions but has been implicated in microtubule interaction. Here, we present the crystal structure of the WD40 domain of human LRRK2 at 2.6-Å resolution, which reveals a seven-bladed WD40 fold. The structure displays a dimeric assembly in the crystal, which we further confirm by measurements in solution. We find that structure-based and PD-associated disease mutations in the WD40 domain including the common G2385R polymorphism mainly compromise dimer formation. Assessment of full-length LRRK2 kinase activity by measuring phosphorylation of Rab10, a member of the family of Rab GTPases known to be important kinase substrates of LRRK2, shows enhancement of kinase activity by several dimerization-defective mutants including G2385R, although dimerization impairment does not always result in kinase activation. Furthermore, mapping of phylogenetically conserved residues onto the WD40 domain structure reveals surface patches that may be important for additional functions of LRRK2. Collectively, our analyses provide insights for understanding the structures and functions of LRRK2 and suggest the potential utility of LRRK2 kinase inhibitors in treating PD patients with WD40 domain mutations.
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