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Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin.

Wilson KP, Yamashita MM, Sintchak MD, Rotstein SH, Murcko MA, Boger J, Thomson JA, Fitzgibbon MJ, Black JR, Navia MA
Acta Crystallogr D Biol Crystallogr 51 511-21 (1995)
Related entries: 1fkj, 1fkl

Cited: 55 times
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Abstract

FK506 (tacrolimus) is a natural product now approved in the US and Japan for organ transplantation. FK506, in complex with its 12 kDa cytosolic receptor (FKBP12), is a potent agonist of immunosuppression through the inhibition of the phosphatase activity of calcineurin. Rapamycin (sirolimus), which is itself an immunosuppressant by a different mechanism, completes with FK506 for binding to FKBP12 and thereby acts as an antagonist of calcineurin inhibition. We have solved the X-ray structure of unliganded FKBP12 and of FKBP12 in complex with FK506 and with rapamycin; these structures show localized differences in conformation and mobility in those regions of the protein that are known, by site-directed mutagenesis, to be involved in calcineurin inhibition. A comparison of 16 additional X-ray structures of FKBP12 in complex with FKBP12-binding ligands, where those structures were determined from different crystal forms with distinct packing arrangements, lends significance to the observed structural variability and suggests that it represents an intrinsic functional characteristic of the protein. Similar differences have been observed for FKBP12 before, but were considered artifacts of crystal-packing interactions. We suggest that immunosuppressive ligands express their differential effects in part by modulating the conformation of FKBP12, in agreement with mutagenesis experiments on the protein, and not simply through differences in the ligand structures themselves.

Articles - 1fkk mentioned but not cited (4)

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Reviews citing this publication (5)

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Articles citing this publication (46)

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Related citations provided by authors (6)

  1. X-Ray Structure of Calcineurin Inhibited by the Immunophilin-Immunosuppressant Fkbp12-Fk506 Complex. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA Cell 82 507- (1995)
  2. Improved Calcineurin Inhibition by Yeast Fkbp12-Drug Complexes. Rotonda J, Burbaum JJ, Chan HK, Marcy AI, Becker JW J. Biol. Chem. 268 7607- (1993)
  3. Fk-506-Binding Protein: Three-Dimensional Structure of the Complex with the Antagonist L-685,818. Becker JW, Rotonda J, Mckeever BM, Chan HK, Marcy AI, Wiederrecht G, Hermes JD, Springer JP J. Mol. Biol. 268 11335- (1993)
  4. Atomic Structures of Human Immunophilin Fkbp12 Complexes with Fk506 and Rapamycin. Van Duyne GD, Standaert RF, Karplus PA, Schreiber SL, Clardy J J. Mol. Biol. 229 105- (1993)
  5. Atomic Structure of the Rapamycin Human Immunophilin Fkbp-12 Complex. Van Duyne GD, Standaert RF, Schreiber SL, Clardy J J. Am. Chem. Soc. 113 7433- (1991)
  6. Atomic Structure of Fkbp-Fk506, an Immunophilin-Immunosuppressant Complex. Van Duyne GD, Standaert RF, Karplus PA, Schreiber SL, Clardy J Science 252 839- (1991)

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