Bierer B E, Somers P K, Wandless T J, Burakoff S J, Schreiber S L
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Science. 1990 Oct 26;250(4980):556-9. doi: 10.1126/science.1700475.
The immunosuppressants FK506 and rapamycin bind to the same immunophilin, FK506 binding protein (FKBP), and inhibit distinct signal transduction pathways in T lymphocytes. A nonnatural immunophilin ligand, 506BD, which contains only the common structural elements of FK506 and rapamycin, was synthesized and found to be a high-affinity ligand of FKBP and a potent inhibitor of FKBP rotamase activity. Whereas 506BD does not interfere with T cell activation, it does block the immunosuppressive effects of both FK506 and rapamycin. Thus, the common immunophilin binding element of these immunosuppressants, which is responsible for rotamase inhibition, is fused to different effector elements, resulting in the inhibition of different signaling pathways. Inhibition of rotamase activity is an insufficient requirement for mediating these effects.
免疫抑制剂FK506和雷帕霉素与同一亲免素FK506结合蛋白（FKBP）结合，并抑制T淋巴细胞中不同的信号转导途径。合成了一种仅包含FK506和雷帕霉素共同结构元件的非天然亲免素配体506BD，发现它是FKBP的高亲和力配体和FKBP旋转异构酶活性的有效抑制剂。虽然506BD不干扰T细胞活化，但它确实能阻断FK506和雷帕霉素的免疫抑制作用。因此，这些免疫抑制剂的共同亲免素结合元件负责旋转异构酶抑制，它与不同的效应元件融合，导致不同信号通路的抑制。抑制旋转异构酶活性对于介导这些效应来说是一个不充分的条件。
