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

• Published in: Journal of molecular biology Vol. 229; no. 1; p. 105
• Main Authors: Van Duyne, G D, Standaert, R F, Karplus, P A, Schreiber, S L, Clardy, J
• Format: Journal Article
• Language: English
• Published: England 05-01-1993
• Subjects: Amino Acid Sequence; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Humans; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - metabolism; Models, Molecular; Molecular Sequence Data; Polyenes - chemistry; Polyenes - metabolism; Protein Structure, Secondary; Sirolimus; Solutions; Tacrolimus - chemistry; Tacrolimus - metabolism; Tacrolimus Binding Proteins; X-Ray Diffraction
• ISSN: 0022-2836
• DOI: 10.1006/jmbi.1993.1012

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.