ArticleThe Journal of biological chemistry2015
Structural and Functional Characterization of the JH2 Pseudokinase Domain of JAK Family Tyrosine Kinase 2 (TYK2).
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 99 citations in OpenAlex.
- First-in-human study of deucravacitinib: A selective, potent, allosteric small-molecule inhibitor of tyrosine kinase 2.Clinical and translational science · 2023Trial
- Modulating pseudokinase conformation from the ATP-binding site.Structure (London, England : 1993) · 2026Article
- The JAK/STAT pathway: a pivotal therapeutic target in disease and advances in natural product modulation.Molecular diversity · 2026Review
- PocketMaster provides a flexible and automated tool for analyzing, clustering, and visualizing structural diversity in protein pockets.Scientific reports · 2026Article
- Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.Journal of medicinal chemistry · 2026Review
- Pharmacological targeting of the JAK-STAT pathway: new concepts and emerging indications.Nature reviews. Drug discovery · 2026Review
- From Convenience to Clinical Efficacy: Selective TYK2 Inhibition in Psoriasis and the Evolving Role of Next-Generation Oral Targeted Therapies.Pharmaceutics · 2026Review
- Structural basis for pseudokinase-mediated regulation of GCN2 in the integrated stress response.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Rare germline JAK/STAT variants in a Korean cohort amplify innate immune responses to vaccination.iScience · 2025Article
- Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community.BMC genomics · 2025Article
- Tyrosine kinase 2 inhibitors in the therapy of inflammatory and autoimmune diseases.Pharmacological reports : PR · 2025Review
- Recent advances and future perspectives in small molecule JAK2 inhibitors.Future medicinal chemistry · 2025Review
- 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
- Differential properties of Janus kinase inhibitors in the treatment of immune-mediated inflammatory diseases.Rheumatology (Oxford, England) · 2024Review
- The oncogenic mechanisms of the Janus kinase-signal transducer and activator of transcription pathway in digestive tract tumors.Cell communication and signaling : CCS · 2024Review
- Targeting TYK2 for Fighting Diseases: Recent Advance of TYK2 Inhibitors.Current medicinal chemistry · 2024Review
- New and emerging oral therapies for psoriasis.Drugs in context · 2024Review
- A novel highly selective allosteric inhibitor of tyrosine kinase 2 (TYK2) can block inflammation- and autoimmune-related pathways.Cell communication and signaling : CCS · 2023Article
- Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies.International journal of molecular sciences · 2023Article
- JAK1 Pseudokinase V666G Mutant Dominantly Impairs JAK3 Phosphorylation and IL-2 Signaling.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
JAK (Janus family of cytoplasmic tyrosine kinases) family tyrosine kinase 2 (TYK2) participates in signaling through cytokine receptors involved in immune responses and inflammation. JAKs are characterized by dual kinase domain: a tyrosine kinase domain (JH1) that is preceded by a pseudokinase domain (JH2). The majority of disease-associated mutations in JAKs map to JH2, demonstrating its central regulatory function. JH2s were considered catalytically inactive, but JAK2 JH2 was found to have low autoregulatory catalytic activity. Whether the other JAK JH2s share ATP binding and enzymatic activity has been unclear. Here we report the crystal structure of TYK2 JH2 in complex with adenosine 5'-O-(thiotriphosphate) (ATP-γS) and characterize its nucleotide binding by biochemical and biophysical methods. TYK2 JH2 did not show phosphotransfer activity, but it binds ATP and the nucleotide binding stabilizes the protein without inducing major conformational changes. Mutation of the JH2 ATP-binding pocket increased basal TYK2 phosphorylation and downstream signaling. The overall structural characteristics of TYK2 JH2 resemble JAK2 JH2, but distinct stabilizing molecular interactions around helix αAL in the activation loop provide a structural basis for differences in substrate access and catalytic activities among JAK family JH2s. The structural and biochemical data suggest that ATP binding is functionally important for both TYK2 and JAK2 JH2s, whereas the regulatory phosphorylation appears to be a unique property of JAK2. Finally, the co-crystal structure of TYK2 JH2 complexed with a small molecule inhibitor demonstrates that JH2 is accessible to ATP-competitive compounds, which offers novel approaches for targeting cytokine signaling as well as potential therapeutic applications.
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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.