ArticleNature structural & molecular biology2012
Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F.
Article in Nature structural & molecular biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.
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109 citing papers in PubMed, 225 citations in OpenAlex.
- Review
- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- Non-receptor tyrosine kinase signaling pathways and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- JAK/STAT signaling in liver disease: a therapeutic target or a context-dependent double-edged sword?Journal of translational medicine · 2026Review
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- From Coffee Alkaloid to Ovarian Targets: An Integrated Computational Framework for Trigonelline in Ovarian Aging.Food science & nutrition · 2026Article
- Germline JAK2 R564Q variants presenting as hereditary thrombocytosis: case report.BJC reports · 2025Article
- JAK2 p.R564 germ line variants associated with hereditary thrombocythemia and hematologic neoplasms.Blood advances · 2025Article
- Deep learning-guided discovery of selective JAK2-JH2 allosteric inhibitors: integration of MLP predictive modeling, BREED-based library design, and computational validation.Frontiers in chemistry · 2025Article
- Dibenzo [a, c] phenazin-11-yl(phenyl) methanone (SBLJ23), a novel selective inhibitor targeting JAK2Oncology research · 2025Article
- Survey for Activating Oncogenic Mutation Variants in Metazoan Germline Genes.Journal of molecular evolution · 2024Article
- Structural basis of MPL activation by thrombopoietin.Blood vessels, thrombosis & hemostasis · 2024Article
- Article
- Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity.Nature communications · 2024Article
- Molecular basis of JAK2 activation in erythropoietin receptor and pathogenic JAK2 signaling.Science advances · 2024Article
- A newly identified 45-kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance.Molecular oncology · 2024Article
- LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy.Kidney international reports · 2024Article
- Next-Generation JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms: Lessons from Structure-Based Drug Discovery Approaches.Blood cancer discovery · 2023Article
- Article
- Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer.Signal transduction and targeted therapy · 2023Review
49 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The protein tyrosine kinase JAK2 mediates signaling through numerous cytokine receptors. JAK2 possesses a pseudokinase domain (JH2) and a tyrosine kinase domain (JH1). Through unknown mechanisms, JH2 regulates the catalytic activity of JH1, and hyperactivating mutations in the JH2 region of human JAK2 cause myeloproliferative neoplasms (MPNs). We showed previously that JAK2 JH2 is, in fact, catalytically active. Here we present crystal structures of human JAK2 JH2, including both wild type and the most prevalent MPN mutant, V617F. The structures reveal that JH2 adopts the fold of a prototypical protein kinase but binds Mg-ATP noncanonically. The structural and biochemical data indicate that the V617F mutation rigidifies α-helix C in the N lobe of JH2, facilitating trans-phosphorylation of JH1. The crystal structures of JH2 afford new opportunities for the design of novel JAK2 therapeutics targeting MPNs.
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