Cyclophilin (CyP) is a binding protein for cyclosporin A (CsA), the immunosuppressive drug to prevent the organ rejection after transplantation. The CyP-CsA complex binds calcineurin, a calmodulin-dependent serine/threonine protein phosphatase in signal transduction pathway towards T-cell activation. CyP is also an enzyme catalyzing the cis-trans isomerization of a peptidyl-prolyl bond (PPIase) and functions as a molecular chaperone involving in protein folding of biological systems. Cyclophilin 40 is a member of the Hsp90 molecular chaperone system that regulates many biological processes such as the steroid hormone signaling pathway. In addition, CyP binds the HIV-1 capsid protein and is required for HIV-1 infectivity.

Ribbon diagram of CyPA-CsA. The structure showed residues 1-3 and 9-11 of CsA (balls and sticks) bind to the hydrophobic pocket of CyPA while residues 4-7 of CsA interact with other molecules of CyP. Thus, a replacement of d-Ala8 of CsA with hydrophilic side chains may improve its water solubility.

The structure of CyPA in complex with substrate AAPF showed that Arg55 is close to the carbonyl nitrogen and thus suggests a novel mechanism -- the protonation on the amide nitrogen of the substrate by Arg55 to facilitate the peptidyl-prolyl cis-trans isomerization.

The structure of CyPA in complex with a 25 amino acid fragment of HIV-1 capsid p24 revealed a trans configuration and a unique glycine backbone conformation of the bound HIV peptide. This unusual binding of the HIV peptide implies that CyP does not function as a PPIase but likely a molecular chaperone in HIV-1 infectivity.