Tissue factor (TF) serves as the central organizing receptor in the macromolecular assembly of the cell surface initiation complex for the coagulation serine protease cascades. We will attempt to solve the three dimensional structure of the functional surface domain of human TF. We will elucidate structure using state-of-the-art X-ray crystallographic methods using co-crystals of TF with Fab fragments of monoclonal antibodies to the C-module of TF and to the N-module of TF. We will expand structure-function interpretations from integration of mutational and biochemical information from Projects IIA and IIB. We will solve the structure of the Fab fragments of the same two selected TF monoclonal antibodies. This will also provide insight into the mechanisms of action by which these antibodies, which have been shown to be functionally effective in vivo, block binding of factor VIIa or block assembly of the ternary complex with substrate respectively. We will attempt to crystallize the actual functional binary complex of TF VIIa and also of factor VIIa through co-crystallization with the Fab fragment of selected monoclonal antibodies to factor VIIa. In addition, the knowledge of TF, a member of the Cytokine Receptor Superfamily of receptors, should provide new information on the general structure and functional relationships of this family of proteins.
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