PDBsum entry: 1fkl

Rotamase

PDB id: 1fkl

Contents

Protein chain

107 a.a. *

Ligands

RAP

Waters ×63

* Residue conservation analysis

PDB id:

1fkl

Name:

Rotamase

Title:

Atomic structure of fkbp12-rapaymycin, an immunophilin- immunosuppressant complex

Structure:

Fk506 binding protein. Chain: a. Synonym: fkbp12, fkbp. Other_details: mr 12,000 daltons

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organ: thymus

Resolution:

1.70Å R-factor: 0.181

Authors:

K.P.Wilson,M.D.Sintchak,J.A.Thomson,M.A.Navia

Key ref:

K.P.Wilson et al. (1995). Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin. Acta Crystallogr D Biol Crystallogr, 51, 511-521. PubMed id: 15299838 DOI: 10.1107/S0907444994014514

Date:

18-Aug-95 Release date: 07-Dec-95

Protein chain

P18203  (FKB1A_BOVIN) -  Peptidyl-prolyl cis-trans isomerase FKBP1A

Seq: 108 a.a.

Struc: 107 a.a.

Enzyme reactions

• Enzyme class: E.C.5.2.1.8 - Peptidylprolyl isomerase.
• Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: cytoplasm (5 terms)
• Biological process: muscle contraction (15 terms)
• Biochemical function: drug binding (4 terms)

Added reference

DOI no: 10.1107/S0907444994014514

Acta Crystallogr D Biol Crystallogr 51:511-521 (1995)

PubMed id: 15299838

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

K.P.Wilson, M.M.Yamashita, M.D.Sintchak, S.H.Rotstein, M.A.Murcko, J.Boger, J.A.Thomson, M.J.Fitzgibbon, J.R.Black, M.A.Navia.

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.

Selected figure(s)

Figure 3.
Fig. 3. Plot of the temperature factors (/I~2) of the Co atoms of te structure of the unlganded bFKBPI2 superimposed on the r.m.s. deiation motion of the Cc~ atoms from the 100 ps dynamics runs on solvated unliganded bFKBP12.

Figure 7.
Fig. 7. Solvent-accessible surface representation of the FKBP12-FK506 complex structure. The surface is color coded with respect to its curvature, from concave (in red) to convex (in blue), as calculated by the program GRASP (Nicholls & Honig, 1992). Side chains for those residues known to be involved in calcineurin inhibition by site-directed mutagenesis studies (Aldape et al., 1992; Yang, Rosen & Schreiber, 1993) are also displayed. A number of suggestive depressions are found n the functionally important region of the complex surrounding the bound ligand, including the 'catcher's mitt' (see text) formed by FK506 and protein residues Asp37, His87 and Ile90. A second depression ivolves residues Arg2 nd Phe46. Ligand-induced conformational changes, or mutations (Aldape et al., 1992; Itoh et al., 1995) in this mobile egion of the protein ould alter the conformation of these surface depressions (or could eliminate them altogether), thereby preventing the binding and inhibition of calcineurin.

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (1995, 51, 511-521) copyright 1995.

Figures were selected by an automated process.