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. 1993 Jan 5;229(1):105-24.
doi: 10.1006/jmbi.1993.1012.

Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin

G D Van Duyne  1 , R F Standaert, P A Karplus, S L Schreiber, J Clardy
Affiliations

Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin

G D Van Duyne et al. J Mol Biol. .

Abstract

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.

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