5l6y
From Proteopedia
il13 in complex with tralokinumab
Structural highlights
Disease[IL13_HUMAN] Defects in IL13 may be a cause of susceptibility to allergic rhinitis (ALRH) [MIM:607154]. Allergic rhinitis is a common disease of complex inheritance and is characterized by mucosal inflammation caused by allergen exposure. Function[IL13_HUMAN] Cytokine. Inhibits inflammatory cytokine production. Synergizes with IL2 in regulating interferon-gamma synthesis. May be critical in regulating inflammatory and immune responses. Publication Abstract from PubMedInterleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Ralpha1, which then recruits IL-4Ralpha to form a heterodimeric receptor complex. IL-13 also binds to IL-13Ralpha2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Ralpha1, IL-4Ralpha and/or IL-13Ralpha2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma. To decipher how tralokinumab inhibits the effects of IL-13, we determined the structure of tralokinumab Fab in complex with human IL-13 to 2 A resolution. The structure analysis reveals that tralokinumab prevents IL-13 from binding to both IL-13Ralpha1 and IL-13Ralpha2. This is supported by biochemical ligand-receptor interaction assay data. The tralokinumab epitope is mainly composed of residues in helices D and A of IL-13. It is mostly light chain complementarity-determining regions that are driving paratope interactions; the variable light complementarity-determining region 2 plays a key role by providing residue contacts for a network of hydrogen bonds and a salt bridge in the core of binding. The key residues within the paratope contributing to binding were identified as Asp50, Asp51, Ser30 and Lys31. This study demonstrates that tralokinumab prevents the IL-13 pharmacodynamic effect by binding to IL-13 helices A and D, thus preventing IL-13 from interacting with IL-13Ralpha1 and IL-13Ralpha2. Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Ralpha1 and IL-13Ralpha2.,Popovic B, Breed J, Rees DG, Gardener MJ, Vinall LM, Kemp B, Spooner J, Keen J, Minter R, Uddin F, Colice G, Wilkinson T, Vaughan T, May RD J Mol Biol. 2016 Dec 9. pii: S0022-2836(16)30534-4. doi:, 10.1016/j.jmb.2016.12.005. PMID:27956146[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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