FK506-binding proteins inhibition

Zeng, B.F., MacDonald, J.R., Bann, J.G., Reck, K., Gambee, J.E., Boswell, B.A. and Bachinger, H.P. (1998) Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-lrans isomerases, is only partially inhibited by FK506. BiochemicalJournal 330, 109-114. 

F.A. Etzkorn, L.A. Stolz, Z.Y. Chang, C.T. Walsh, Role of the cyclosporin-A-cyclophilin complex, FK506-FK506-binding protein complex and calcineurin in the inhibition of T-cell signal transduction, Curr. Opin. Struct. Biol. 3 (1993) 929-933. 

The immimosuppressive effect of cyclosporin and FK506 could not initially be explained by these observations. Only with the discovery that cyclosporin and FK506 achieve their immunosuppressive effect via inhibition of calcineurin did it become clear that the immimosuppression is mediated by a complex reaction chain involving calcineurin. It was shown that the complexes of cyclosporin/cyclophilin and FK506/ FK506 binding protein bind to calcineurin and inhibit the phosphatase activity of the latter. 

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

Sirolimus, a macrolide antibiotic, in one mode of action, binds to FK506-binding protein (FKBP12), inhibiting the activation of mammalian target of rapamycin (mTOR), which, in turn, blocks the cellular transition from G, to the S phase of the cell cycle (35). Sirolimus was approved by the Food and Drug Administration (FDA) in 1999 for the prevention of renal... 

The finding that both classes of prolyl isomerases, the cyclophilins and the FK506-binding proteins, are strongly inhibited by immunosuppres-... 

There are several examples that illustrate the potential of SAR by NMR. As noted earlier, FK506 binding protein (FKBP) inhibits cal-cineurin and blocks T-cell activation when complexedtothe immunosuppressant FK506. This protein was used as a target for SAR by... 

Transcription of interleukin 2 is inhibited as one of the consequences of inhibition of calcineurin by cyclosporin/cyclophilin and FK506/FK506-binding protein as an extracellular signal, interleukin 2 can stimulate proliferation of lymphocytes. This discovery made it clear that the protein phosphatase calcineurin has an essential role in signal transduction in T lymphocytes and that these processes are severely impeded by cyclosporin and FK506. 

Figure 4.9. Schematic representation of immunosuppressant-immunophilin complex interactions. CyPs bind CsA to form a complex in which both components undergo change in structure. This complex binds to, and inhibits, calcineurin (CnA, A subunit CnB, B subunit CaM, camodulin) in a calcium-dependent manner. FK506-binding protein complxes with FK506 or rapamycin (Rapa). FKBP-FK506 also binds calcineurin. The target of FKBP-rapamycin is unknown but is presumed to be different from cacineurin.

Like cyclosporine, tacrolimus inhibits T-cell activation by inhibiting calcineurin. Tacrolimus binds to an intracellular protein, FK506-binding protein—12 (FKBP-12), an... 

Johnson, K. L., and Lawen, A. (1999). Rapamycin inhibits didemnin B-induced apoptosis in human HL-60 cells Evidence for the possible involvement of FK506-binding protein 25. Immunol. Cell Biol. 77, 242-248. 

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