Interleukin-1 Receptor Antagonist Protein: Solution Secondary Structure from NOE's and 1H« and 13C« Chemical Shifts

Inter leukinla and interleukin-ip are two polypeptides which share a significant number of inflammatory, immunological and pathological properties (for a review see [1]). Importantly, these dissimilar 17 kDa proteins bind to two classes of interleukin-1 receptors, resulting in the mediation of several immune and inflammatory responses and in the induction of a variety of biological changes in neurologic, metabolic, hematologic, and endocrinologic systems [1]. In addition to IL-loc and IL-1(3, an interleukin-1 receptor antagonist protein (termed either IRAP or IL-lra) has been isolated, characterized, cloned and expressed in E. coli [2-4]. This newer member of the IL-1 gene family is a naturally occurring inhibitor of the interleukin-1 receptor [2,4], and represents the first described naturally occurring cytokine that functions entirely as a specific receptor antagonist. Site-directed mutagenesis [5-7] and protein modification [6] studies have identified three regions of IL-1 that are involved in either receptor binding or transmission of the biological response upon binding. For IRAP, it can be hypothesized that the regions of structure important for receptor binding are maintained, but that the region or regions responsible for eliciting the response are somehow different. To this end, we have begun an intensive program to determine the solution structure of IRAP using NMR spectroscopy. Since the solution [8-12] and crystalline [13,14] structures of IL-lp have been determined, direct comparisons can be made between IRAP and IL-lp. This may lead to a correlation between structural and biological differences.