Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP

@article{Choi1996StructureOT,
  title={Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP},
  author={Jungwon Choi and Jie Chen and Stuart L. Schreiber and Jon Clardy},
  journal={Science},
  year={1996},
  volume={273},
  pages={239 - 242}
}
  • Jungwon Choi, Jie Chen, +1 author J. Clardy
  • Published 1996
  • Biology, Medicine
  • Science
Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive… Expand

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References

SHOWING 1-10 OF 34 REFERENCES
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. Expand
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 theExpand
A mammalian protein targeted by G1-arresting rapamycin–receptor complex
TLDR
A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Expand
RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs
TLDR
It is proposed that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins, which were originally identified by mutations that confer rapamycin resistance in yeast. Expand
X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex
TLDR
The ternary complex described here represents the three-dimensional structure of a Ser/Thr protein phosphatase and provides a structural basis for understanding calcineurin inhibition by FKBP12-FK506. Expand
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. Expand
Control of p70 S6 kinase by kinase activity of FRAP in vivo
TLDR
FRAP is a rapamycin-sensitive regulator of p70S6k in vivo and that the kinase activity of FRAP is required for this regulation, and it is shown that FRAP autophosphorylates in vitro. Expand
Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue.
TLDR
It is shown that the FRAP Ser2035-->Ala mutant displays similar binding affinity when compared with the wild-type protein, whereas all other mutations at this site, including mimics of phosphoserine, abolish binding, presumably due to either unfavorable steric interactions or induced conformational changes. Expand
A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin
CYCLOSPORIN A and the newly discovered immunosuppressant, FK-506, are potent inhibitors of T cell activation1. In addition to their clinical importance in the prevention of allograft rejection,Expand
TOR Mutations Confer Rapamycin Resistance by Preventing Interaction with FKBP12-Rapamycin (*)
TLDR
These studies confirm that the TOR proteins are direct targets of FKBP12-rapamycin, reveal that drug-resistant mutations prevent this association, and define structural features of these complexes. Expand
...
1
2
3
4
...