Tyrosine kinase 2 pseudokinase domain (JH2) (TYK2 JH2)

Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family, essential for mediating signaling from receptors for type I interferons, IL-12, and IL-23 (UniProt P29597). The TYK2 protein structure includes a catalytic JH1 domain and a regulatory pseudokinase JH2 domain. The JH2 domain, despite lacking catalytic activity, is a key regulatory element that maintains the JH1 domain in an inactive state through autoinhibitory interactions (Burke et al., 2019). Dysregulation of TYK2-mediated signaling is implicated in the pathogenesis of several autoimmune and inflammatory conditions, such as psoriasis and systemic lupus erythematosus (NIH/NCBI). Unlike traditional JAK inhibitors that target the highly conserved ATP-binding site in the JH1 domain, allosteric inhibitors specifically target the JH2 domain. This approach provides high selectivity for TYK2 over JAK1, JAK2, and JAK3, minimizing off-target effects associated with pan-JAK inhibition, such as cytopenia or lipid changes (FDA Sotyktu Label). Drugs like deucravacitinib bind to the JH2 domain to lock the enzyme in its inactive conformation, thereby inhibiting the phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. This selective inhibition effectively modulates the inflammatory response while maintaining a favorable safety profile compared to first-generation JAK inhibitors.

Other names

TYK2 JH2 domainJanus kinase 2 homology domain 2TYK2 pseudokinase domainTyrosine kinase 2 JH2

Allosteric inhibition by binding to the pseudokinase (JH2) domain, which stabilizes the autoinhibitory conformation of the catalytic (JH1) domain, preventing its activation.