CONFORMATION OF FK506 IN X-RAY STRUCTURES OF ITS COMPLEXES WITH HUMANRECOMBINANT FKBP12 MUTANTS

In the X-ray structure of the FK506 complex with an FKBP12 double-muta nt (R42K+H87V), the ligand is seen to adopt a conformation in its effe ctor domain region that is distinctly altered compared to that found i n the complex structure with native FKBP12. Nonetheless, molecular dyn amics simulations indicate that the FK506 conformations seen in the na tive and mutant complex structures are energetically equivalent. Our o bservations suggest caution in the application of drug design strategi es for calcineurin-mediated immunosuppressants that are based on mimic ry of the FK506 conformation seen in the structure of the ligand compl ex with native FKBP12.