STRUCTURE STUDIES ON PROTEINS THAT MODULATE IL-10 ACTION

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Description: (From the applicant's abstract) The overall goal of this research is to identify the structural basis for protein-protein interactions that modulate interleukin 10 (IL-10) biological activities by elucidating crystal structures of IL-10 complexed with its cell surface receptors, and several Fab fragments of neutralizing antibodies using X-ray diffraction techniques. These data will be used to design IL-10 mutants that enhance or prevent IL-10/IL-10 receptor interactions as well as mutants that change the geometry and/or the stoichiometry of the IL-10 receptor-ligand complex. Formation of a complex consisting of IL-10, a high affinity receptor (IL-10Ralpha), and a signal transducing receptor (IL-10Rbeta) is required for the generation of IL-10 biological activities that suppress TH1-dependent, cell-mediated immune responses. As a result of these activities, IL-10 is a very promising protein therapeutic for the treatment of chronic inflammatory diseases. IL-10 is currently in phase III clinical trials for Crohn's disease and phase II trials for rheumatoid arthritis that affects 40 million people and costs the country over 65 billion dollars annually in work disability. In addition to its immunosuppressive role, IL-10 has been implicated as an autocrine growth factor responsible in the pathogenesis of several B-cell malignancies. Thus, antagonists of IL-10 have potential therapeutic applications.