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

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family that plays a critical role in mediating signaling pathways for pro-inflammatory cytokines, including interleukin-23 (IL-23), IL-12, and Type I interferons (IFNs) (UniProt P29597). The JH2 regulatory domain, also known as the pseudokinase domain, is a non-catalytic region of the protein that naturally regulates the activity of the adjacent catalytic JH1 domain (Wrobleski et al., 2019, J. Med. Chem.). In recent years, the JH2 domain has emerged as a high-priority therapeutic target because its unique structural features allow for the development of allosteric inhibitors. These inhibitors, such as deucravacitinib, bind to the JH2 domain to stabilize an autoinhibitory interaction with the JH1 domain, effectively locking the enzyme in an inactive state (Chimalakonda et al., 2021, Dermatol Ther.). This allosteric approach provides superior selectivity for TYK2 over other JAK family members (JAK1, JAK2, and JAK3), which share highly similar ATP-binding sites in their catalytic domains. Consequently, targeting the TYK2 JH2 domain offers a safer profile for treating chronic inflammatory conditions like psoriasis, psoriatic arthritis, and systemic lupus erythematosus by avoiding the hematologic and metabolic side effects often seen with non-selective JAK inhibitors (Burke et al., 2019, Sci. Signal.).

Other names

Tyrosine kinase 2 regulatory domainTYK2 pseudokinase domainJanus kinase 2 pseudokinase domainTYK2 JH2 domain

Allosteric inhibition of Tyrosine kinase 2 (TYK2) by binding to the JH2 pseudokinase domain, which induces a conformational change that stabilizes the autoinhibitory interaction between the JH2 and JH1 domains, thereby preventing the catalytic activity of the JH1 domain and blocking downstream signaling of IL-23, IL-12, and Type I interferons.