XRAY STUDIES OF EPO AND IL2 RECEPTOR COMPLEXES

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION: (adapted from applicant's abstract) The long term goal of this study is to understand the recognition, interaction, assembly and signal transduction of cytokine receptors. A major issue is how signal a generated from the extracellular binding of a cytokine hormone to its receptor can lead to a biological response of cell activation or proliferation inside the cell. Cytokine hormones appear to effect a signal by homodimerization or heterodimerization of the receptor ectodomains. Such oligomerization leads to phosphorylation events inside the cell that provides a second message for signaling to the nucleus. The first major goal is to determine how peptide agonists and antagonists of erythropoietin can activate or inhibit erythropoietin receptor (EPOR) function that leads to production of red blood cells. The aim is to determine how small molecule mimetics bind to the "hot spot" or functional epitope on the receptor surface in comparison to the interaction with the natural hormone, EPO. Another goal is to investigate whether a small molecule, non-peptidic agonist can be designed from the structure of the peptide mimetic-EPOR complex. Such small molecules would be invaluable in the design of orally available drugs. Whether there are multiple or limited modes of dimerization that can lead to signal transduction will also be addressed. The second major project involves a related cytokine receptor, interleukin 2 (IL-2R). IL-2R is more complex and consists of three chains, that form a trimolecular complex on interaction with IL-2. A key question is how the receptor is assembled from hormone-specific chains and a chain that is common to other cytokine receptors. The crystallographic study of IL-2 mutants and various forms of the receptor complex should give insights into the structure and function of this key receptor in T cell growth and proliferation.