| STRUCTURE |
A research team has rounded out more than a decade of studies on the mechanism of immunosuppressant drugs by obtaining the crystal structure of a ternary complex formed by the drug cyclosporin A, the binding protein cyclophilin, and the enzyme calcineurin. The work could lead to better agents for immune suppression and a more in-depth understanding of the binding interactions and molecular mechanisms that underlie immunity. The mechanism of action of immunosuppressive drugs like cyclosporin A and FK506--taken by transplant patients to prevent tissue rejection--has been a topic of longstanding study by a number of research teams. The endogenous molecular target is the enzyme calcineurin, a phosphatase enzyme in the signaling pathway leading to immune-cell activation. The two ternary complexes that form are as follows: One forms between cyclosporin A, the immunophilin (immunosuppressant binding protein) cyclophilin, and calcineurin. Another complex forms between FK506, the immunophilin FK binding protein (FKBP), and the common calcineurin target. Calcineurin is "the only case of a common protein target shared by two structurally distinct protein-ligand complexes. "Nature is teaching us an important lesson--that there is more than one solution to the problem of molecular recognition of the same protein target." Authors have now closed the circle, in a sense, by obtaining the crystal structure of the other calcineurin-based ternary complex--the one formed by cyclosporin A, cyclophilin, and calcineurin. The structure shows that cyclosporin-cyclophilin and FK506-FKBP--despite the lack of any significant structural similarity--bind to the same site in calcineurin. About four-fifths of the calcineurin residues involved in interacting with the former complex are also involved in binding to the latter--although some of the common residues interact with the two drug-immunophilin complexes in a strikingly different manner. It is daunting to imagine how these two complexes have come to existence during evolution, considering that cyclosporin A is produced by fungi while FK506 is of bacterial origin. Authors hypothesize that the common binding site on calcineurin is likely also involved in the binding of calcineurin to endogenous substrates--helping to explain the enzyme's relatively narrow substrate specificity. |
| UPDATE | 09.02 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |