Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52.

@article{Gopalakrishnan2012EvaluationOS,
  title={Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52.},
  author={R. Gopalakrishnan and C. Kozany and S. Gaali and C. Kress and B. Hoogeland and A. Bracher and F. Hausch},
  journal={Journal of medicinal chemistry},
  year={2012},
  volume={55 9},
  pages={
          4114-22
        }
}
The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51… Expand
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TLDR
A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FK BP52, and the molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography. Expand
Crystal structures of the free and ligand-bound FK1-FK2 domain segment of FKBP52 reveal a flexible inter-domain hinge.
TLDR
Two co-crystal structures of FKBP52 are presented in complex with the prototypic ligand FK506 and a synthetic analog thereof, which revealed the molecular interactions in great detail and enabled in-depth comparison with the corresponding complexes of the other cytosolic FKBPs, FkBP51 and FK BP12. Expand
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Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into molecular mechanisms based on multiple simulation technologies
TLDR
Calculated calculations of residue-based free energy decomposition not only recognize the hot interaction spot of inhibitors with FKBP51, but also display that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP play significant role in stronger binding of 3JR and 3JQ to FK BP51 than 3JP. Expand
Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control.
TLDR
This work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. Expand
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TLDR
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TLDR
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TLDR
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Differential conformational dynamics in the closely homologous FK506-binding domains of FKBP51 and FKBP52
TLDR
To examine whether differences in conformational dynamics/plasticity might correlate with changes in the reported receptor activities, 15N-NMR relaxation measurements were carried out on the N-terminal FK BP domains of FKBP51 and FKB52 as well as their residue-swapped variants. Expand
Rapid, Structure-Based Exploration of Pipecolic Acid Amides as Novel Selective Antagonists of the FK506-Binding Protein 51.
TLDR
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Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52.
TLDR
A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FK BP52, and the molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography. Expand
Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90.
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These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors. Expand
Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin.
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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. Expand
FK506-binding Proteins 51 and 52 Differentially Regulate Dynein Interaction and Nuclear Translocation of the Glucocorticoid Receptor in Mammalian Cells*
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The mechanisms of the regulatory system FKBP51/FKBP52 discovered in yeast also operate in mammals to modulate hormone binding of the receptor and differential regulation of dynein association and nuclear translocation contributes to the effects of the two immunophilins on the glucocorticoid receptor in mammals. Expand
Noncatalytic Role of the FKBP52 Peptidyl-Prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling
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The results suggest that the FK1 domain, and in particular the loop overhanging the catalytic pocket, is critically involved in receptor interactions and receptor activity. Expand
Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506.
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Results show that immunosuppressive ligands can alter GR hormone-binding function by changing the TPR protein composition of receptor complexes and that TPR proteins exert a hierarchical effect on this GR function in the following order: FKBP52 > PP5 > FK BP51. Expand
DESIGN, SYNTHESIS, AND KINETIC EVALUATION OF HIGH-AFFINITY FKBP LIGANDS AND THE X-RAY CRYSTAL-STRUCTURES OF THEIR COMPLEXES WITH FKBP12.
The design and synthesis of high-affinity FKBP12 ligands is described. These compounds potently inhibit the cis-trans-peptidylprolyl isomerase (rotamase) activity catalyzed by FKBP12 with inhibitionExpand
The Hsp90‐binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo
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The influences of immunophilins on hormone‐dependent gene activation in the Saccharomyces cerevisiae model for glucocorticoid receptor (GR) function is examined in vivo. Expand
FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells
TLDR
It is reported that the Hsp90 cochaperone FKBP51 is upregulated in LAPC-4 AI tumors grown in castrated mice and a molecular mechanism by which FK BP51 regulates AR activity is described, which provides an attractive target for inhibiting AR activity in prostate cancer cells. Expand
The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress
TLDR
Results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. Expand
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