Solution structure of the cyclosporin A/cyclophilin complex by NMR.
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Theriault Y, Logan TM, Meadows R, Yu L, Olejniczak ET, Holzman TF, Simmer RL, Fesik SW
Solution structure of the cyclosporin A/cyclophilin complex by NMR.
Nature. 1993 Jan 7;361(6407):88-91.
- PubMed ID
- 8421500 [ View in PubMed]
- Abstract
Cyclosporin A, a cyclic undecapeptide, is a potent immunosuppressant that binds to a peptidyl-prolyl cis-trans isomerase of 165 amino acids, cyclophilin. The cyclosporin A/cyclophilin complex inhibits the calcium- and calmodulin-dependent phosphatase, calcineurin, resulting in a failure to activate genes encoding interleukin-2 and other lymphokines. The three-dimensional structures of uncomplexed cyclophilin, a tetrapeptide/cyclophilin complex, and cyclosporin A when bound to cyclophilin 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 complex and is analysed in terms of the binding interactions and structure/activity relationships for CsA analogues.