32-Indolyl ether derivatives of ascomycin: three-dimensional structures of complexes with FK506-binding protein.

摘要: 32-Indole ether derivatives of tacrolimus and ascomycin retain the potent immunosuppressive activity their parent compounds but display reduced toxicity. In addition, complexes with 12-kDa FK506-binding protein (FKBP) form more stable phosphatase calcineurin, molecular target these drugs. We have solved three-dimensional structures FKBP two 32-indolyl ascomycin. The macrolide are remarkably similar to those seen in indole groups project away from body complex, multiple conformations observed for linkage as well a nearby peptide suggesting apparent flexibility parts structure. Comparison that ternary complex FKBP, suggests interact binding site comprising elements both calcineurin alpha- beta-chains this interaction is responsible increased stability complexes.