The chemistry of signal transduction

Several disciplines, including chemical ecology, seek to understand the molecular basis of information transfer in biological systems, and general molecular strategies are beginning to emerge. Often these strategies are discovered by a careful analysis of natural products and their biological effects. Cyclosporin A, FK506, and rapamycin are produced by soil microorganisms and are being used or considered as clinical immunosuppressive agents. They interrupt the cytoplasmic portion of T-cell signaling by forming a complex with a binding protein--FKBP12 in the case of FK506 and rapamycin and cyclophilin A (CyPA) in the case of cyclosporin A (CsA). This complex in turn inhibits a protein target, and the best understood target is calcineurin, which is inhibited by FK506-FKBP12 and CyPA-CsA. Mutational and structural studies help define how FK506-FKBP12 interacts with calcineurin, and the results of these studies are summarized. The existence of strong FK506-FKBP12 binding suggests that FK506 is mimicking some natural ligand for FKBP12. Synthetic and structural studies to probe this mimicry are also described.