FK506/FKBPs structure

Figure 7 (A) A divalent ligand for the protein FK506 binding protein (FKBP). (B) The reference system is the complex formed between FKBP and the two fragments, M2 and M9, which independently bind In the two different pockets filled by the divalent composite molecule. FKBP structure is from PDB (1FKS).

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. 

B. Structure of the FKBP-FK506-Calcineurin Ternary Complex. 276... 

In 1991, Schreiber and Clardy and associates reported the crystal structure of FK506 bound with FKBP (Van Duyne et al., 1991a). While... 

The overall structure of the FKBP-FK506 binary complex is unperturbed on binding to calcineurin, and no gross structural perturbations could be detected in calcineurin at the resolution of these studies, aside from the displacement of the autoinhibitory domain seen in the study with full-length calcineurin. However, on binding, 400 to 550 A2 of solvent-accessible surface area is buried for each component (Stoddard and Flick, 1996). The C15-C21 region of FK506 is seen to be inserted... 

The crystal structure of the cyclophilin-CsA-calcineurin ternary structure has yet to be resolved but the ternary structure formed by rapamycin-mediated interactions between FKBP12 and the 12-kDa fKBP-rapamycin binding (FRB) domain of the 289-kDa FRAP protein has been determined with 2.7 A resolution (Choi et al, 1996), which has more recently been refined to 2.2 A resolution (Liang et al, 1999). The structure of this complex is shown in Fig. 6 (see color insert). Several similarities as well as differences in the overall mode of interaction can be seen relative to what is observed with the FKBP-FK506-cal-cineurin structure. As was seen with the FKBP-FK506 calcineurin ternary complex, there are no overall gross conformational changes... 

Kay, J. E. (1996). Structure-function relationships in the FK506-binding protein (FKBP) family of peptidylprolyl cis-trans isomerases. Biochem.J. 314, 361-385. 

Van Duyne, G. D., Standaert, R. F., Karplus, P. A., Schreiber, S. L., and Clardy, J. (1991a). Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex. 

Moore et al, 1991). The secondary structure of FKBP is about 35% /3 sheet and less than 10% helix. FKBP has an unprecedented antiparallel /3-sheet folding topology that results in the crossing of the two loops that connect strands of the sheet. This structural motif creates a hydrophobic cavity that is lined by a conserved array of six of the nine aromatic amino acids of the proteins. This cavity is the binding site for FK506 and probably is the isomerase active site. 

Also see color figure.) Structures for the immunosuppressant, FK506 (tacrolimus). Tacrolimus is a macrolide isolated from Streptomyces tsukubaensis. Shown from left to right in approximately the same orientation are the simple line structure, a stick- structure, and a space-filling structure. The stick and space-filling structures are based on the 3-dimensional structure of the molecule bound to the immunophilin FKBP. Protein data bank designation IFKF. 

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