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1: Nature. 1993 Jan 7;361(6407):88-91.Click here to read Links

Solution structure of the cyclosporin A/cyclophilin complex by NMR.

Thériault Y, Logan TM, Meadows R, Yu L, Olejniczak ET, Holzman TF, Simmer RL, Fesik SW.

Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064.

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.

PMID: 8421500 [PubMed - indexed for MEDLINE]

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