title: Solution structure of the cyclosporin A/cyclophilin complex by NMR.
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.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: Y
authors.initials: Y
authors.lastname: Thériault
authors.forename: T M
authors.initials: TM
authors.lastname: Logan
authors.forename: R
authors.initials: R
authors.lastname: Meadows
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: E T
authors.initials: ET
authors.lastname: Olejniczak
authors.forename: T F
authors.initials: TF
authors.lastname: Holzman
authors.forename: R L
authors.initials: RL
authors.lastname: Simmer
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry*; D003524:Cyclosporins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019696:Peptidylprolyl Isomerase; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D003524:Cyclosporins; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase