FK-506 is a potent immunosuppressant that forms a high affinity complex (Ki = 0.2 nM) with FK-506 binding protein 12 (FKBP12). This complex inhibits the activity of the calcium/calmodulin-dependent protein phosphatase, calcineurin, leading to disruption of T-cell activation.1 Synthetic ligand of FKBP (SLF) is a cell-permeable analog of FK-506 that binds tightly to FKBP but lacks the ability to inhibit calcineurin.2 By itself, SLF does not exhibit a significant cellular response. However, homodimers of SLF or heterodimers with another protein ligand, provide a method to promote the dimerization of ligand-specific fusion proteins to induce signaling events within a cellular environment.3,2 For example, SLF monomers connected with a 10-atom linker activates Fas signaling via Fas-FKBP fusion proteins with an EC50 of 6 nM.3
1
Dumont, F.J. FK506, An immunosuppressant targeting calcineurin function. Curr Med Chem7731-748(2000).
2
Braun, P.D., Barglow, K.T., Lin, Y., et al. A bifunctional molecule that displays context-dependent cellular activity. J Am Chem Soc1257575-7580(2003).
3
Amara, J.F., Clackson, T., Rivera, V.M., et al. A versatile synthetic dimerizer for the regulation of protein-protein interactions. Proc Natl Acad Sci USA9410618-10623(1997).
Dumont, F.J. FK506, An immunosuppressant targeting calcineurin function. Curr Med Chem7731-748(2000).
Braun, P.D., Barglow, K.T., Lin, Y., et al. A bifunctional molecule that displays context-dependent cellular activity. J Am Chem Soc1257575-7580(2003).
Amara, J.F., Clackson, T., Rivera, V.M., et al. A versatile synthetic dimerizer for the regulation of protein-protein interactions. Proc Natl Acad Sci USA9410618-10623(1997).
SLF is available in the following screening
library: