Atomic Structures of the Human Immunophilin FKBP-12 Complexes with FK506 and Rapamycin

High resolution structures for the complexes formed by the immunosuppressive agents FK506 and rapamycin with the human immunophilin FKBP-12 have been determined by X-ray diffraction. FKBP-12 has a novel fold comprised of a five-stranded β-sheet wrapping around a short α-helix with an overall conical shape. Both FK506 and rapamycin bind in the cavity defined by the β-sheet, α-helix and three loops. Both FK506 and rapamycin bind in similar fashions with a set of hydrogen bonds and an unusual carbonyl binding pocket. Bound FK506 has different conformation than free (crystalline) FK506 while rapamycin's bound conformation is virtually identical to that of unbound rapamycin. FKBP-12 is a peptidyl-prolyl isomerase (PPIase), and the structures of the complexes suggest ways in which this catalytic activity could operate. The different complexes are active in suppressing different steps of T cell activation, an activity seemingly unconnected with the PPIase activity.