CONFORMATIONAL POLYMORPHISM OF CYCLOSPORINE-A

Background: Cyclosporin A (CsA) is a cyclic undecapeptide fungal metab olite with immunosuppressive properties, widely used in transplant sur gery. It forms a tight complex with the ubiquitous 18 kDa cytosolic pr otein cyclophilin A (CypA). The conformation of CsA in this complex, a s studied by NMR or X-ray crystallography, is very different from that of free CsA. Another, different conformation of CsA has been found in a complex with an antibody fragment (Fab). Results: A detailed compar ison of the conformations of experimentally determined structures of p rotein-bound CsA is presented. The X-ray and NMR structures of CsA-Cyp A complexes are similar. The Fab-bound conformation of CsA, as determi ned by X-ray crystallography, is significantly different from the cycl ophilin-bound conformation. The protein-CsA interactions in both the F ab and CypA complexes involve five hydrogen bonds, and the buried CsA surface areas are 395 Angstrom(2) and 300 Angstrom(2), respectively. H owever, the CsA-protein interactions involve rather different side cha in contacts in the two complexes. Conclusions: The structural results presented here are consistent with CypA recognizing and binding a popu lation of CsA molecules which are in the required CypA-binding conform ation. In contrast, the X-ray structures of the Fab complex with CsA s uggest that in this case there is mutual adaptation of both receptor a nd ligand during complex formation.