title: Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin.
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.
authors.affiliation: Department of Chemistry, Cornell University Ithaca, NY 14853-1301.
authors.forename: G D
authors.initials: GD
authors.lastname: Van Duyne
authors.forename: R F
authors.initials: RF
authors.lastname: Standaert
authors.forename: P A
authors.initials: PA
authors.lastname: Karplus
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: J
authors.initials: J
authors.lastname: Clardy
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011090:Polyenes / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D020123:Sirolimus; D012996:Solutions; D016559:Tacrolimus / Q000737:chemistry* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D014961:X-Ray Diffraction
chemical_list: D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D012996:Solutions; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus