The long range goal of this project is expanding our knowledge of immunophilins and their complexes. Immunophilins are proteins that, among other things, form complexes with immunosuppressive drugs, and these immunophilin-drug complexes are responsible for inhibiting the immune response. In the FKBP family of immunophilins, the subject of this proposal, the complex of FKBP-12 with FK506 inhibits the TCR signal of T cell activation and the complex of FKBP-12 with rapamycin inhibits the LKR signal of T cell activation. The proposed work involves determining the structures of new immunophilins, particularly FKBP-13 and FKBP-26, and complexes at atomic resolution using the technique of single crystal X-ray diffraction. Since the immunophilin-drug complexes must interact with a partner, protein, an additional goal would be to determine the structure of the ternary complex formed by an immunophilin-drug-partner protein. A detailed knowledge of the atomic structure of these complexes would have important applications in medicine and basic science. For example, it would be possible to design a new generation of immunosuppressive drugs from first principles based on the structures determined. Moderating the immune response would also be important for medical issues other than transplant rejection. For example, autoimmune diseases such as rheumatoid arthritis or psoriasis could be treated by the same general strategy of inhibiting the activation of T cells. The structures of the complexes would be important for basic science and would provide much needed information on the pathway of cytoplasmic signal transduction.
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