Tyrosine kinase 2, Janus homology 2 pseudokinase regulatory domain (TYK2 JH2)

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases that plays a pivotal role in the signaling pathways of pro-inflammatory cytokines, including interleukin-23 (IL-23), interleukin-12 (IL-12), and Type I interferons [1, 6, 10]. The TYK2 protein contains a catalytic JH1 domain and a regulatory JH2 pseudokinase domain [1, 6]. While the JH2 domain lacks enzymatic activity, it is essential for regulating the activity of the JH1 domain through an autoinhibitory mechanism [1, 11]. Dysregulation of TYK2-mediated signaling is strongly associated with the pathogenesis of various autoimmune and inflammatory disorders, such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus [3, 4, 6]. Traditional JAK inhibitors often target the highly conserved ATP-binding site of the JH1 domain, leading to off-target effects and safety concerns like thrombosis and cytopenia [2, 14, 21]. In contrast, novel allosteric inhibitors specifically bind to the JH2 pseudokinase domain, stabilizing the enzyme in its inactive conformation [1, 3, 13]. This approach provides high selectivity for TYK2 over other JAK isoforms (JAK1, JAK2, and JAK3), resulting in a more favorable safety profile and effective therapeutic outcomes for patients with immune-mediated diseases [2, 14, 24].

Other names

TYK2 JH2 domainTYK2 pseudokinase domainJanus homology 2 domain of TYK2TYK2 regulatory domainJH2 domain of Tyrosine kinase 2

Allosteric inhibition by binding to the JH2 pseudokinase domain, which stabilizes the autoinhibited conformation of the TYK2 protein and prevents the activation of the JH1 catalytic domain [1, 3, 13].