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Solution structure of the cyclosporin A/cyclophilin complex by NMR

Abstract

CYCLOSPORIN A, a cyclic undecapeptide, is a potent immuno-suppressant that binds to a peptidyl–prolyl cis–trans isomerase1,2 of 165 amino acids, cyclophilin3. The cyclosporin A/cyclophilin complex inhibits the calcium- and calmodulin-dependent phos-phatase, calcineurin4, resulting in a failure to activate genes encoding interleukin-2 and other lymphokines5,6. The three-dimensional structures of uncomplexed cyclophilin7, a tetrapeptide/cyclophilin complex8,9, and cyclosporin A when bound to cyclophilin10,11 have been reported. However, the structure of the cyclosporin A/cyclophilin complex has not been determined. Here we present the solution structure of the cyclosporin A/cyclophilin complex obtained by heteronuclear three-dimensional NMR spectroscopy. The structure, one of the largest determined by NMR, differs from proposed models of the complex12–14 and is analysed in terms of the binding interactions and structure/activity relationships for CsA analogues15,16.

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Thériault, Y., Logan, T., Meadows, R. et al. Solution structure of the cyclosporin A/cyclophilin complex by NMR. Nature 361, 88–91 (1993). https://doi.org/10.1038/361088a0

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