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Publication Abstract from PubMed

Interleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor alpha chain (IL3Ralpha) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique "open" and classical "closed" conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas "open-like" IL3Ralpha mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a "double hit" cytokine receptor blockade.

Dual mechanism of interleukin-3 receptor blockade by an anti-cancer antibody.,Broughton SE, Hercus TR, Hardy MP, McClure BJ, Nero TL, Dottore M, Huynh H, Braley H, Barry EF, Kan WL, Dhagat U, Scotney P, Hartman D, Busfield SJ, Owczarek CM, Nash AD, Wilson NJ, Parker MW, Lopez AF Cell Rep. 2014 Jul 24;8(2):410-9. doi: 10.1016/j.celrep.2014.06.038. Epub 2014, Jul 17. PMID:25043189^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.