5t5w
From Proteopedia
Structure of an affinity matured lambda-IFN/IFN-lambdaR1/IL-10Rbeta receptor complex
Structural highlights
DiseaseI10R2_HUMAN Autosomal recessive early-onset inflammatory bowel disease. The disease is caused by mutations affecting the gene represented in this entry. FunctionI10R2_HUMAN 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.[1] [2] Publication Abstract from PubMedType III interferons (IFN-lambdas) signal through a heterodimeric receptor complex composed of the IFN-lambdaR1 subunit, specific for IFN-lambdas, and interleukin-10Rbeta (IL-10Rbeta), which is shared by multiple cytokines in the IL-10 superfamily. Low affinity of IL-10Rbeta for cytokines has impeded efforts aimed at crystallizing cytokine-receptor complexes. We used yeast surface display to engineer a higher-affinity IFN-lambda variant, H11, which enabled crystallization of the ternary complex. The structure revealed that IL-10Rbeta uses a network of tyrosine residues as hydrophobic anchor points to engage IL-10 family cytokines that present complementary hydrophobic binding patches, explaining its role as both a cross-reactive but cytokine-specific receptor. H11 elicited increased anti-proliferative and antiviral activities in vitro and in vivo. In contrast, engineered higher-affinity type I IFNs did not increase antiviral potency over wild-type type I IFNs. Our findings provide insight into cytokine recognition by the IL-10R family and highlight the plasticity of type III interferon signaling and its therapeutic potential. The IFN-lambda-IFN-lambdaR1-IL-10Rbeta Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity.,Mendoza JL, Schneider WM, Hoffmann HH, Vercauteren K, Jude KM, Xiong A, Moraga I, Horton TM, Glenn JS, de Jong YP, Rice CM, Garcia KC Immunity. 2017 Mar 21;46(3):379-392. doi: 10.1016/j.immuni.2017.02.017. PMID:28329704[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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