Department of Chemistry, Cornell University Ithaca, NY 14853-1301.
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 beta-sheet wrapping around a short alpha-helix with an overall conical shape. Both FK506 and rapamycin bind in the cavity defined by the beta-sheet, alpha-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 a 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.