Tyrosine kinase 2 (TYK2) Janus homology 2 (JH2) domain (TYK2 JH2)

The Tyrosine kinase 2 (TYK2) Janus homology 2 (JH2) domain is a regulatory pseudokinase domain within the TYK2 protein, a member of the Janus kinase (JAK) family (UniProt P29597). While the JH1 domain is the catalytic site, the JH2 domain lacks enzymatic activity and instead functions as an allosteric regulator that maintains the enzyme in an inactive state (Burke et al., 2019, Science). TYK2 is essential for signaling pathways of Type I interferons, IL-12, and IL-23, which are central to the pathogenesis of autoimmune diseases like psoriasis and systemic lupus erythematosus (Chimalakonda et al., 2021, Arthritis & Rheumatology). Therapeutic targeting of the JH2 domain via allosteric inhibitors, such as deucravacitinib, allows for high selectivity for TYK2 over JAK1, JAK2, and JAK3 (Wrobleski et al., 2019, J. Med. Chem.). This selectivity profile minimizes off-target effects like anemia, neutropenia, and lipid elevations typically associated with orthosteric JAK inhibitors that target the conserved JH1 ATP-binding pocket (Sotyktu FDA Label, 2022). By stabilizing the autoinhibitory conformation, these drugs prevent the phosphorylation of downstream STAT proteins, thereby dampening the inflammatory response.

Other names

TYK2 pseudokinase domainJanus kinase 2 homology domain of TYK2JH2 domain of Tyrosine kinase 2

Allosteric inhibition by binding to the pseudokinase (JH2) domain, which induces a conformational change that stabilizes the autoinhibitory interaction with the catalytic (JH1) domain, thereby preventing kinase activation (Burke et al., 2019; Wrobleski et al., 2019).