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

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family that mediates signaling for several pro-inflammatory cytokines, including interleukin-23 (IL-23), IL-12, and Type I interferons (UniProt P29597). The JH2 pseudokinase domain is a non-catalytic regulatory region of the TYK2 protein that naturally inhibits the activity of the adjacent JH1 catalytic domain (PubMed: 30185904). Therapeutic targeting of the JH2 domain represents an allosteric approach to drug design, where small molecules bind to the JH2 site to stabilize its autoinhibitory conformation, thereby preventing the activation of the JH1 domain (PubMed: 35324898). This mechanism offers high selectivity for TYK2 over other JAK family members (JAK1, JAK2, and JAK3), which lack similar regulatory pockets or have different structural requirements (FDA: Sotyktu Prescribing Information). By inhibiting TYK2 signaling, these drugs effectively treat autoimmune and inflammatory conditions such as psoriasis and lupus while minimizing the off-target side effects typically associated with broad JAK inhibitors (PubMed: 34133869). This domain-specific targeting has revolutionized the development of JAK inhibitors by providing a pathway to avoid the hematological and metabolic toxicities often seen with orthosteric JH1 inhibitors.

Other names

TYK2 pseudokinase domainTYK2 JH2 domainTyrosine kinase 2 pseudokinase domainJanus homology 2 domain of TYK2

Allosteric inhibition by binding to the JH2 pseudokinase domain to stabilize the autoinhibitory interaction with the JH1 catalytic domain, thereby preventing kinase activation (PubMed: 30185904).