The goal of the proposal is to understand the structural basis for the specific recognition of cytokines by their receptors. The crystallographic studies of interferon-q (IFN-q) and its complexes with a neutralizing Fab fragment as well as with the extracellular fragments of the two recombinant human interferon-q receptors are in progress. Comparison of the atomic coordinates of all forms of IFN-q will elucidate the conformational changes that occur upon binding to the receptor. Understanding the structural recognition mechanisms that induce the anti- viral and cytostatic properties of IFN-q is critical for designing molecules which modulate its activity. Attempts will be made to use the structural results to design and test peptidomimetics or humanized Fab antagonists of IFN-q. Antagonists of IFN-q may have therapeutic value in the treatment of autoimmune diseases, chronic inflammation and allograft rejection. Substantial preliminary data have been presented to suggest that the stated goals are feasible.
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