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 isomeraseof 165 amino acids, cyclophilin The cyclosporin A/cyclophilin complex inhibits the calcium- and calmodulin-dependent phos-phatase, 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 cyclophilinhave 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 complexand is analysed in terms of the binding interactions and structure/activity relationships for CsA analogues © 1993 Nature Publishing Group.