X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex

@article{Griffith1995XraySO,
  title={X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex},
  author={James P. Griffith and Joseph L. Kim and Eunice EunKyeong Kim and Michael D. Sintchak and John A. Thomson and Matthew J. Fitzgibbon and Mark A. Fleming and Paul R. Caron and Kathy Hsiao and Manuel A. Navia},
  journal={Cell},
  year={1995},
  volume={82},
  pages={507-522}
}
View on Elsevier
doi.org
725 Citations
Highly Influential Citations
27
Background Citations
162
Methods Citations
16
Results Citations
2

Figures and Tables from this paper

725 Citations

Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin
  • Lei Jin, S. Harrison
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The crystal structure of a Cyp/CsA/Cn ternary complex is reported, which accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications ofCsA alter immunosuppressive activity.
Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex
TLDR
The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule.
Calcineurin. Structure, function, and inhibition.
TLDR
The X-ray structure of an FKPB12-FK506-calcineurin AB ternary complex reveals that FKBP12-FX506 binds in a hydophobic groove between the calcineur in A catalytic and the regulatory B subunit, in accord with biochemical and genetic studies on inhibitor action.
A proposed molecular model for the interaction of calcineurin with the cyclosporin A-cyclophilin A complex.
  • M. Ivery
  • Chemistry, Biology
    Bioorganic & medicinal chemistry
  • 1999
Competitive and slow-binding inhibition of calcineurin by drug x immunophilin complexes.
TLDR
Results are consistent with the hypothesis that both classes of drug x immunophilin complexes interact with a common locus on CN which excludes phosphopeptide binding in the enzyme's active site.
Structures of calcineurin and its complexes with immunophilins-immunosuppressants.
  • H. Ke, Q. Huai
  • Biology, Chemistry
    Biochemical and biophysical research communications
  • 2003
Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes
  • Q. Huai, Hwa-young Kim, H. Ke
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin–immunosuppressant.
Calcineurin-immunosuppressor complexes.
Delineation of the calcineurin‐interacting region of cyclophilin B
TLDR
Results strongly suggest that the three amino acids G77, D155, and D158 are directly involved in the interaction of CyPB/CsA with calcineurin, in agreement with their exposed position.
Different roles of Loop 7 in inhibition of calcineurin.
...
...

References

SHOWING 1-10 OF 91 REFERENCES
The latch region of calcineurin B is involved in both immunosuppressant-immunophilin complex docking and phosphatase activation
Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex
The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the…
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
Characterization of the calcium‐binding sites of calcineurin B
Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin.
TLDR
It is suggested 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.
Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin.
TLDR
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 and suggest ways in which this catalytic activity could operate.
Charged surface residues of FKBP12 participate in formation of the FKBP12-FK506-calcineurin complex.
Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A.
TLDR
The results show that calcineurin is a target of drug-immunophilin complexes in vivo and establish a physiological role for calcium-dependent serine/threonine phosphatase in T-cell activation.
Conformation of Fk506 in X-Ray Structures of its Complexes with Human Recombinant Fkbp12 Mutants
Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation
TLDR
It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
...
...