ArticleProceedings of the National Academy of Sciences of the United States of America2022
Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 53 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson's disease.The Biochemical journal · 2026Article
- Nanobodies targeting the Epstein-Barr virus EBNA1 DNA binding domain inhibit tumor growth.Journal of nanobiotechnology · 2026Article
- LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Nanobodies targeting hnRNPA2/B1 and tau.bioRxiv : the preprint server for biology · 2025Article
- Allosteric Anti-KLK4 Antibody Development for Targeted Anti-cancer Effects in Ovarian Carcinoma.Journal of molecular biology · 2025Article
- Developing nanobodies as allosteric molecular chaperones of glucocerebrosidase function.Nature communications · 2025Article
- Development of Galectin-7-Specific Nanobodies: Implications for Immunotherapy and Molecular Imaging in Cancer.Journal of medicinal chemistry · 2025Article
- Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody.eLife · 2025Article
- Single-Chain Nanobody Inhibition of Notch and Avidity Enhancement Utilizing the β-Pore-Forming Toxin Aerolysin.ACS chemical biology · 2025Article
- Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.eLife · 2024Article
- Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation - Relevance to psychiatric and neurodevelopmental illness, and implications for treatment.Neurobiology of stress · 2024Article
- Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years.Journal of nanobiotechnology · 2024Review
- Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin.bioRxiv : the preprint server for biology · 2024Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- A designed ankyrin-repeat protein that targets Parkinson's disease-associated LRRK2.The Journal of biological chemistry · 2024Article
- Article
- Recombinant Antibody Fragments for Immunotherapy of Parkinson's Disease.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2024Review
- Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.Cell discovery · 2024Article
- Recombinant Antibody Fragments for Neurological Disorders: An Update.Current neuropharmacology · 2024Review
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are a leading cause of the inherited form of Parkinson's disease (PD), while LRRK2 overactivation is also associated with the more common idiopathic form of PD. LRRK2 is a large multidomain protein, including a GTPase as well as a Ser/Thr protein kinase domain. Common, disease-causing mutations increase LRRK2 kinase activity, presenting LRRK2 as an attractive target for drug discovery. Currently, drug development has mainly focused on ATP-competitive kinase inhibitors. Here, we report the identification and characterization of a variety of nanobodies that bind to different LRRK2 domains and inhibit or activate LRRK2 in cells and in in vitro. Importantly, nanobodies were identified that inhibit LRRK2 kinase activity while binding to a site that is topographically distinct from the active site and thus act through an allosteric inhibitory mechanism that does not involve binding to the ATP pocket or even to the kinase domain. Moreover, while certain nanobodies completely inhibit the LRRK2 kinase activity, we also identified nanobodies that specifically inhibit the phosphorylation of Rab protein substrates. Finally, in contrast to current type I kinase inhibitors, the studied kinase-inhibitory nanobodies did not induce LRRK2 microtubule association. These comprehensively characterized nanobodies represent versatile tools to study the LRRK2 function and mechanism and can pave the way toward novel diagnostic and therapeutic strategies for PD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.