32-indolyl ether derivatives of ascomycin: Three-dimensional structures ofcomplexes with FK506-binding protein

32-Indole ether derivatives of tacrolimus and ascomycin retain the potent i mmunosuppressive activity of their parent compounds but display reduced tox icity. In addition, their complexes with the 12-kDa FK506-binding protein ( FKBP) form more stable complexes with the protein phosphatase calcineurin, the molecular target of these drugs. We have solved the three-dimensional s tructures of the FKBP complexes with two 32-indolyl derivatives of ascomyci n. The structures of the protein and the macrolide are remarkably similar t o those seen in the complexes with tacrolimus and ascomycin. The indole gro ups project away from the body of the complex, and multiple conformations a re observed for the linkage to these groups as well as for a nearby peptide suggesting apparent flexibility in these parts of the structure. Compariso n of these structures with that of the ternary complex of calcineurin, FKBP , ana tacrolimus suggests that the indole groups interact with a binding si te comprising elements of both the calcineurin alpha- and beta-chains and t hat this interaction is responsible for the increased stability of these co mplexes.