ArticleeLife2026
Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease.
Article in eLife, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Deep mutational scanning reveals pharmacologically relevant insights into TYK2 signaling and disease.eLife · 2026Article
- Exome sequencing directly implicates 68 genes in inflammatory bowel disease.medRxiv : the preprint server for health sciences · 2026Article
- Uncovering the molecular basis of kinase activity and substrate recognition with phospho-PCA.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
24 authors.
Funding
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Abstract
Tyrosine kinase 2 (TYK2) is a genetically defined target for autoimmune disease, with first-generation inhibitors showing clinical success in some but not all associated indications. A deeper understanding of TYK2 structure-function relationships, protein-ligand interactions, and the impact of human variants could inform next-generation therapeutics. Here, we applied deep mutational scanning (DMS) to assess >23,000 amino acid substitutions across two TYK2 functions: interferon alpha (IFN-α) signaling and protein abundance. This enabled high-resolution structure-function mapping and the identification of novel allosteric sites. By coupling DMS with inhibitor treatment, we uncovered variants that modulate compound potency. We also show that human variants - both common and rare - that are protective against autoimmune phenotypes reduce TYK2 protein abundance. Together, these findings demonstrate that DMS can prospectively reveal novel druggable sites, clarify structure-activity relationships (SAR), and highlight TYK2 degradation as a potential therapeutic strategy in autoimmunity.
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