This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interleukin 5 (IL5) is the major hematopoietic cytokine responsible for differentiation, proliferation, migration, and activation of eosinophils. Eosinophils play key roles in the innate immune response and are also important players in pathological states such as asthma. IL5 acts on eosinophils through a cell surface receptor that contains alpha and beta chains, with alpha being primarily responsible for ligand binding and beta for signal transduction. As a first step in understanding how IL5 recruits alpha and beta chains and assembles them into a complex competent for intracellular signaling, we have crystallized the complex of IL5 with the extracellular domain of the receptor alpha chain. Our collaborators in the Chaiken laboratory have many years of experience in studying IL5-receptor interactions, and our structure will prove extremely useful in evaluating the data they have amassed concerning the development of agonists and antagonists and the effects of mutagenesis. Our long term goals include the crystallization of the IL5-alpha-beta complex, crystallization of the receptor with various peptide agonists and antagonists, and correlation of our structural results with functional data on receptor assembly acquired by the Chaiken group. A thorough structural and mechanistic understanding of how receptor assembly proceeds and leads to signaling will prove useful in the development of therapeutics for allergic inflammations such as asthma.
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