Consortia for High-Throughput-Enabled Structural Biology Partnerships (U01)

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The Immune Function Network (IFN), a consortium of immunologists, geneticists, computational biochemists, and high throughput structural biologists, is committed to the coordinated structural, in vitro biochemical and in vivo ftinctional analyses of the secreted molecules and ectodomains of cell surface molecules that control adaptive and innate immunity. These molecules are validated targets for immime-based therapies to treat a wide range of autoimmune diseases, infectious diseases and cancers, and are indeed therapeutics in their own right. The IFN, subscribes to a series of underlying principles: 1) target selection supports hypothesis-driven structural biology by identifying unique primary amino acid sequence signatures that predict unique structural features, which are in turn responsible for unique biological function; 2) the high resolution structures of these molecules are exceptionally revealing as they inform on oligomeric state, valency, specificity and general architectural features, all of which are fundamental mechanistic contributors to immune function; 3) these structures can be readily exploited by biochemical and computational approaches to guide the generation of molecules with specifically altered biochemical and biophysical properties; 4) these "surgically-defined" mutants represent novel reagents that will lead to new mechanistic insights in in vitro cellbased assays and in vivo animal models of disease; 5) the molecules predicted to be most informative will guide the generation of knock-in mouse models to provide in vivo structure-function relationships for innate and adaptive immunity. This "Atoms-to-Animals" approach represents the next step in the evolution of Structural Biology as it maximally leverages structural information and provides a comprehensive and powerful paradigm for the study of normal, pathological, and therapeutic immune responses.