6weo

IL-22 Signaling Complex with IL-22R1 and IL-10Rbeta

spinqualitylabelsall models 6weo, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6weo is a 36 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: BMA, FUC, GOL, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function I10R2_MOUSE Shared cell surface receptor required for the activation of five class 2 cytokines: IL10, IL22, IL26, IL28, and IFNL1. The IFNLR1/IL10RB dimer is a receptor for the cytokine ligands IFNL2 and IFNL3 and mediates their antiviral activity. The ligand/receptor complex stimulate the activation of the JAK/STAT signaling pathway leading to the expression of IFN-stimulated genes (ISG), which contribute to the antiviral state (By similarity). Publication Abstract from PubMed Interleukin-22 (IL-22) acts on epithelial cells to promote tissue protection and regeneration, but can also elicit pro-inflammatory effects, contributing to disease pathology. Here, we engineered a high-affinity IL-22 super-agonist that enabled the structure determination of the IL-22-IL-22Ralpha-IL-10Rbeta ternary complex to a resolution of 2.6 A. Using structure-based design, we systematically destabilized the IL-22-IL-10Rbeta binding interface to create partial agonist analogs that decoupled downstream STAT1 and STAT3 signaling. The extent of STAT bias elicited by a single ligand varied across tissues, ranging from full STAT3-biased agonism to STAT1/3 antagonism, correlating with IL-10Rbeta expression levels. In vivo, this tissue-selective signaling drove tissue protection in the pancreas and gastrointestinal tract without inducing local or systemic inflammation, thereby uncoupling these opposing effects of IL-22 signaling. Our findings provide insight into the mechanisms underlying the cytokine pleiotropy and illustrate how differential receptor expression levels and STAT response thresholds can be synthetically exploited to endow pleiotropic cytokines with enhanced functional specificity. The tissue protective functions of interleukin-22 can be decoupled from pro-inflammatory actions through structure-based design.,Saxton RA, Henneberg LT, Calafiore M, Su L, Jude KM, Hanash AM, Garcia KC Immunity. 2021 Apr 13;54(4):660-672.e9. doi: 10.1016/j.immuni.2021.03.008. PMID:33852830 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Interleukin 3D structures

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