Janus kinase 1 pseudokinase domain (JH2) (JAK1 JH2)

Janus kinase 1 (JAK1) is a critical non-receptor tyrosine kinase that mediates signaling for various pro-inflammatory cytokines, including the interleukin-6 (IL-6) family and Type I/II interferons (UniProt P23458). The protein contains two tandem kinase domains: the catalytic JH1 domain and the pseudokinase JH2 domain. While the JH2 domain lacks significant catalytic activity, it serves as a vital regulatory module that maintains the kinase in an autoinhibited state in the absence of cytokine stimulation (Lupardus et al., PNAS 2014). Mutations in the JH2 domain, such as V658F, are known to cause constitutive activation of JAK1, contributing to hematopoietic malignancies and inflammatory disorders (PubMed: 24550270). Modern drug discovery has shifted toward targeting the JH2 domain with allosteric inhibitors to achieve greater selectivity over other JAK family members, particularly JAK2, to avoid hematological side effects like anemia (Nature Communications, 2022). These allosteric inhibitors, such as BMS-986416, bind to the JH2 ATP-binding site and stabilize the autoinhibitory interaction with the JH1 domain, thereby preventing downstream STAT phosphorylation. This approach is currently being explored for the treatment of autoimmune conditions like rheumatoid arthritis and atopic dermatitis, offering a potentially safer profile than traditional orthosteric inhibitors.

Other names

JAK1 JH2 domainJanus kinase 1 regulatory domainJAK1 pseudokinase domainJanus kinase 1 JH2

Allosteric inhibition of the catalytic JH1 domain through binding and stabilization of the pseudokinase JH2 domain.