4i77
Lebrikizumab Fab bound to IL-13
Structural highlights
DiseaseIL13_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. FunctionIL13_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 PubMedThe cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma. The effects of IL-13 are mediated via a pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13Ralpha1 and IL-4Ralpha. Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma. Here we report the molecular structure of IL-13 in complex with the Fab from Lebrikizumab by X-ray crystallography at 1.9A resolution. We show that Lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Ralpha. In addition, we use site-directed mutations to identify the most important antibody contributors to binding. Our studies define key features of Lebrikizumab binding and its mechanism of action that may contribute to its clinical effects. Structural Basis of Signaling Blockade by Anti-IL-13 Antibody Lebrikizumab.,Ultsch M, Bevers J, Nakamura G, Vandlen R, Kelley RF, Wu LC, Eigenbrot C J Mol Biol. 2013 Jan 25. pii: S0022-2836(13)00040-5. doi:, 10.1016/j.jmb.2013.01.024. PMID:23357170[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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