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PDBsum entry 1fkk

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Rotamase PDB id
1fkk
Jmol
Contents
Protein chain
107 a.a. *
Ligands
SO4
Waters ×67
* Residue conservation analysis
PDB id:
1fkk
Name: Rotamase
Title: Atomic structure of fkbp12, an immunophilin binding protein
Structure: Fk506 binding protein. Chain: a. Synonym: fkbp12. Other_details: mr 12,000 daltons
Source: Bos taurus. Cattle. Organism_taxid: 9913. Organ: thymus
Resolution:
2.20Å     R-factor:   0.158    
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    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P18203  (FKB1A_BOVIN) -  Peptidyl-prolyl cis-trans isomerase FKBP1A
Seq:
Struc:
108 a.a.
107 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.5.2.1.8  - Peptidylprolyl isomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Peptidylproline (omega=180) = peptidylproline (omega=0)
Peptidylproline (omega=180)
= peptidylproline (omega=0)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   3 terms 
  Biological process     chaperone-mediated protein folding   5 terms 
  Biochemical function     isomerase activity     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.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
18366641 A.Ceymann, M.Horstmann, P.Ehses, K.Schweimer, A.K.Paschke, M.Steinert, and C.Faber (2008).
Solution structure of the Legionella pneumophila Mip-rapamycin complex.
  BMC Struct Biol, 8, 17.
PDB code: 2vcd
18214965 J.A.Somarelli, S.Y.Lee, J.Skolnick, and R.J.Herrera (2008).
Structure-based classification of 45 FK506-binding proteins.
  Proteins, 72, 197-208.  
18029417 T.Ikura, and N.Ito (2007).
Requirements for peptidyl-prolyl isomerization activity: a comprehensive mutational analysis of the substrate-binding cavity of FK506-binding protein 12.
  Protein Sci, 16, 2618-2625.  
16844742 J.Wang, Y.Deng, and B.Roux (2006).
Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials.
  Biophys J, 91, 2798-2814.  
15356344 G.Gopalan, Z.He, Y.Balmer, P.Romano, R.Gupta, A.Héroux, B.B.Buchanan, K.Swaminathan, and S.Luan (2004).
Structural analysis uncovers a role for redox in regulating FKBP13, an immunophilin of the chloroplast thylakoid lumen.
  Proc Natl Acad Sci U S A, 101, 13945-13950.
PDB code: 1u79
14997571 M.Zacharias (2004).
Rapid protein-ligand docking using soft modes from molecular dynamics simulations to account for protein deformability: binding of FK506 to FKBP.
  Proteins, 54, 759-767.  
12538866 C.R.Sinars, J.Cheung-Flynn, R.A.Rimerman, J.G.Scammell, D.F.Smith, and J.Clardy (2003).
Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes.
  Proc Natl Acad Sci U S A, 100, 868-873.
PDB codes: 1kt0 1kt1
14581219 F.Sun, P.Li, Y.Ding, L.Wang, M.Bartlam, C.Shu, B.Shen, H.Jiang, S.Li, and Z.Rao (2003).
Design and structure-based study of new potential FKBP12 inhibitors.
  Biophys J, 85, 3194-3201.
PDB codes: 1j4h 1j4i
12674506 J.H.Helbig, B.König, H.Knospe, B.Bubert, C.Yu, C.P.Lück, A.Riboldi-Tunnicliffe, R.Hilgenfeld, E.Jacobs, J.Hacker, and G.Fischer (2003).
The PPIase active site of Legionella pneumophila Mip protein is involved in the infection of eukaryotic host cells.
  Biol Chem, 384, 125-137.  
12952945 M.S.Alphey, R.A.Williams, J.C.Mottram, G.H.Coombs, and W.N.Hunter (2003).
The crystal structure of Leishmania major 3-mercaptopyruvate sulfurtransferase. A three-domain architecture with a serine protease-like triad at the active site.
  J Biol Chem, 278, 48219-48227.
PDB code: 1okg
11751578 P.J.Pereira, M.C.Vega, E.González-Rey, R.Fernández-Carazo, S.Macedo-Ribeiro, F.X.Gomis-Rüth, A.González, and M.Coll (2002).
Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed alpha-helix.
  EMBO Rep, 3, 88-94.
PDB code: 1jvw
11514681 A.Korepanova, C.Douglas, I.Leyngold, and T.M.Logan (2001).
N-terminal extension changes the folding mechanism of the FK506-binding protein.
  Protein Sci, 10, 1905-1910.  
11524681 A.Riboldi-Tunnicliffe, B.König, S.Jessen, M.S.Weiss, J.Rahfeld, J.Hacker, G.Fischer, and R.Hilgenfeld (2001).
Crystal structure of Mip, a prolylisomerase from Legionella pneumophila.
  Nat Struct Biol, 8, 779-783.
PDB code: 1fd9
10025408 M.Huse, Y.G.Chen, J.Massagué, and J.Kuriyan (1999).
Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12.
  Cell, 96, 425-436.
PDB code: 1b6c
9164465 C.Brenner, P.Garrison, J.Gilmour, D.Peisach, D.Ringe, G.A.Petsko, and J.M.Lowenstein (1997).
Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins.
  Nat Struct Biol, 4, 231-238.
PDB codes: 3rhn 4rhn 5rhn 6rhn
8994877 B.L.Stoddard, and K.E.Flick (1996).
Calcineurin-immunosuppressor complexes.
  Curr Opin Struct Biol, 6, 770-775.  
8785272 N.D.Silva, and F.G.Prendergast (1996).
Tryptophan dynamics of the FK506 binding protein: time-resolved fluorescence and simulations.
  Biophys J, 70, 1122-1137.  
  8563622 S.Itoh, and M.A.Navia (1995).
Structure comparison of native and mutant human recombinant FKBP12 complexes with the immunosuppressant drug FK506 (tacrolimus).
  Protein Sci, 4, 2261-2268.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.