Conformation of FK506 in X-ray structures of its complexes with human recombinant FKBP12 mutants

In the X-ray structure of the FK506 complex with an FKBP12 double-mutant (R42K+H87V), the ligand is seen to adopt a conformation in its effector domain region that is distinctly altered compared to that found in the complex structure with native FKBP12. Nonetheless, molecular dynamics simulations indicate that the FK506 conformations seen in the native and mutant complex structures are energetically equivalent. Our observations suggest caution in the application of drug design strategies for calcineurin-mediated immunosuppressants that are based on mimicry of the FK506 conformation seen in the structure of the ligand complex with native FKBP12.