Interaction of cyclosporin A and two cyclosporin analogs with cyclophilin: relationship between structure and binding.
The immunosuppressant drug cyclosporin A exists as various conformers in water. Up to 1 h is needed to reach maximum complex formation after mixing the drug with its receptor, cyclophilin, or an antibody, indicating that only a fraction of the conformers in aqueous solution adopts a conformation suitable for binding. In the present study we compare the binding behavior of cyclosporin to that of two analogs, using a biosensor instrument (BIAcore, Pharmacia). The amount of complex formation was measured as a function of time after adding the peptides to cyclophilin. The equilibrium affinity constants of cyclophilin for these analogs have been measured. The slow binding of cyclosporin to cyclophilin compared to the instant binding of the cyclosporin analogs supports the hypothesis that cyclophilin recognizes a well defined conformation of cyclosporin that exists in water prior to binding.
Zeder-Lutz
G
G
Institut de Biologie Moléculaire et Cellulaire du CNRS, Laboratoire d'Immunochimie, Strasbourg, France.
Van Regenmortel
M H
MH
Wenger
R
R
Altschuh
D
D
D000591:Amino Acid Isomerases / Q000737:chemistry*; D002352:Carrier Proteins / Q000737:chemistry*; D002846:Chromatography, Affinity; D016572:Cyclosporine / Q000737:chemistry*; D003524:Cyclosporins / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D019696:Peptidylprolyl Isomerase; D011485:Protein Binding; D011487:Protein Conformation; D012710:Serum Albumin, Bovine / Q000737:chemistry
D002352:Carrier Proteins; D003524:Cyclosporins; D007202:Indicators and Reagents; D012710:Serum Albumin, Bovine; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase