FKBPs

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

Sirolimus (SRL), also termed rapamycin is a macrolide lactone isolated from the ascomycete species Stre-ptomyces hygroscopicus. After binding to its cytosolic receptor FKBP-12 the resulting complex inhibits the multifunctional serine-threonine kinase mTOR (mammalian target of rapamycin). Inhibition of mTOR prevents activation of the p70S6 kinase and successive... 

Tacrolimus (TRL), in the past also named FK506, belongs to the group of macrolides and is produced by a special actinomycete species. TRL binds to its cytosolic receptor FKBP-12, however, it also blocks calcineurin activity and subsequently cytokine synthesis. 

Tliese immunosuppressants increase the activity of RyRl by deprivation of FKBP12. Their effect on RyR2, which binds FKBP12/12.6, is controversial. RyR3 could bind FKBP 12 with unchanged activity. 

FK-506 binding protein (FKBP) iigand, FK-506 binding protein (FKBP) iigand. 

Burkhard P, Hommell U, Sanner M, Walkinshaw MD. The discovery of steroids and other novel FKBP inhibitors using a molecular docking program. J Mol Biol 1999 287 853-8. 

Fe-TPAA Fe(III)-tris[N-(2-pyridylmethyl)-2-aminoethyl] amine Fe-TPEN Fe(II)-tetrakis-N,N,N, N -(2-pyridyl methyl-2-aminoethyl)amine FFA Free fatty acids FGF Fibroblast growth factor FID Flame ionization detector FITC Fluorescein isothiocyanate FKBP FK506-binding protein FLAP 5-lipoxygenase-activating protein... 

Petros AM, Kawai M, Luly JR, Fesik SW. Conformation of two nonimmunosuppressive FK506 analogs when bound to FKBP by isotope-filtered NMR. FEBS Lett 1992 308 309-314. 

Example of Scheme C Inhibition of Calcineurin by FKBP-Inhibitor Complexes... 

Figure 6.17 Cartoon depicting the interactions of FKBP with inhibitor and the subsequent binding of the FKBP Inhibitor binary complex to the enzyme calcineurin (E).

Addition of the L-732,531 FKBP binary complex to a calcineurin activity assay resulted in increasingly nonlinear progress curves with increasing binary complex concentration. The htting of the data to Equation (6.3) revealed an inhibitor concentration effect on v-, as well as on vs and obs, consistent with a two-step mechanism of inhibition as in scheme C of Figure 6.3. Salowe and Hermes analyzed the concentration-response effects of the binary complex on v, and determined an IC50 of 0.90 pM that, after correction for I.S I/A (assuming competitive inhibition), yielded a A) value for the inhibitor encounter complex of 625 nM. 

Peptidyl-prolyl cis-trans isomerase (PPI, cyclophilins/FKBPs) (EC5.3.4.1)... 

Zeng, B.F., MacDonald, J.R., Bann, J.G., Reck, K., Gambee, J.E., Boswell, B.A. and Bachinger, H.P. (1998) Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-lrans isomerases, is only partially inhibited by FK506. BiochemicalJournal 330, 109-114. 

Wulfing, C., Lombardero, J. and Pluckthun, A. (1994) An Escherichia coli protein consisting of a domain homologous to FK506-binding proteins (FKBP) and a new metal binding motif. Journal of Biological Chemistry 269, 2895-2901. 

AGb. We successfully applied this expression to correlate observed binding affinities for series of inhibitors with thrombin,18 HTV-RT,28 and FKBP.20... 

Immunophilin is the generic term for a binding protein for an immunosuppressive agent, and all currently known immunophilins belong to the cyclophilin or FKBP families. The two families of immunophilins— like the small molecules they bind—don t have any readily apparent relationship. FKBP12 and CyPA have no sequence similarity, CsA does not inhibit FKBP12, and FK506 does not inhibit CyPA. 

Both NMR and x-ray studies have been done on free FKBP12, CyPA, and a variety of complexes (30). These studies have been reviewed recently, and the remainder of this paper will focus on relatively recent work in the FKBP area (30). Unfortunately, there are no structural studies on the FKBP12-FK506-caldneurin or CyPA-CsA-caldneurin complexes, so our understanding of the interactions is indirect and incomplete. Nevertheless, the outline, if not the complete details, of an answer is apparent. 

The structural analysis of the 40s loop is more complex. There are only minor differences at residues 38 and 43-45, but from residue 39 to residue 42 the FKBP13 backbone is displaced by up to 2 A from that of FKBP12. How can the extensive modifications of the chimeric FKBP result in a... 

FE FKBP female equivalent FK506-binding protein... 

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