FKBP:FK506 complex, structure

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

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... 

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. 

Figure 4.9. Schematic representation of immunosuppressant-immunophilin complex interactions. CyPs bind CsA to form a complex in which both components undergo change in structure. This complex binds to, and inhibits, calcineurin (CnA, A subunit CnB, B subunit CaM, camodulin) in a calcium-dependent manner. FK506-binding protein complxes with FK506 or rapamycin (Rapa). FKBP-FK506 also binds calcineurin. The target of FKBP-rapamycin is unknown but is presumed to be different from cacineurin.

Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex, Science 1991, 252, 839-842. 

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 structures of FKBP12 (in complex with FK506), FKBP25 (in complex with rapamycin), and FKBP52 (the N-terminal domain) are on file at the Brookhaven Protein Data Bank. The protein structures and rotamase domains of these three FKBPs, sans ligands, are depicted in Figure 5 for comparison and reference in the following discussion of the FKBPs. 

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