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Multidimensional NMR Studies of Immunosuppressant/Immunophilin Complexes

  • Chapter
NMR of Proteins

Part of the book series: Topics in Molecular and Structural Biology ((TMSB))

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Abstract

Cyclosporin A (CsA) and FK506 are two chemically unrelated immunosuppressants (Figure 4.1) that act in a similar way by blocking specific signal transduction pathways at an early stage of T-cell activation. They inhibit the transcription of genes that produce interleukins (IL-2, IL-3, IL-4), granulocyte-macrophage colony stimulating factor, and interferon-γ (Bierer et al., 1990a; Dumont et al., 1990a) by inhibiting specific transcriptional regulators such as nuclear factor of activated T cells (NF-AT) (Emmel et al., 1989). Although CsA and FK506 have similar biological activities, they bind to different cellular receptors, termed immunophilins. CsA binds to cyclophilin (17.8 kD, 165 aa) (Handschumacher et al., 1984), and FK506 binds to FKBP (11.8 kD, 107 aa) (Harding et al., 1989; Siekierka et al., 1989). Both cyclophilin and FKBP are peptidyl-prolyl cis-trans isomerases (PPIase) that are inhibited by CsA (Fischer et al., 1989; Takahashi et al., 1989) or FK506 (Harding et al., 1989; Siekierka et al., 1989), respectively. In an initial attempt to explain the immunosuppressant activity of CsA and FK506, it was hypothesized that PPIase inhibition was the cause of immunosuppression by inhibiting the folding of proteins involved in the early stages of T-cell activation. However, several pieces of evidence now suggest that the inhibition of PPIase activity is insufficient to cause an immunosuppressive effect (Bierer et al., 1990b).

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  1. Stephen W. Fesik
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  1. Laboratory of Chemical Physics, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

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Fesik, S.W., Neri, P. (1993). Multidimensional NMR Studies of Immunosuppressant/Immunophilin Complexes. In: Clore, G.M., Gronenborn, A.M. (eds) NMR of Proteins. Topics in Molecular and Structural Biology. Palgrave, London. https://doi.org/10.1007/978-1-349-12749-8_4

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  • DOI: https://doi.org/10.1007/978-1-349-12749-8_4

  • Publisher Name: Palgrave, London

  • Print ISBN: 978-1-349-12751-1

  • Online ISBN: 978-1-349-12749-8

  • eBook Packages: EngineeringEngineering (R0)

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