Solution structure of the cyclosporin A/cyclophilin complex by NMR.
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.
Thériault
Y
Y
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064.
Logan
T M
TM
Meadows
R
R
Yu
L
L
Olejniczak
E T
ET
Holzman
T F
TF
Simmer
R L
RL
Fesik
S W
SW
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
D002352:Carrier Proteins; D003524:Cyclosporins; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase