CRYSTAL-STRUCTURE OF MURINE CYCLOPHILIN-C COMPLEXED WITH IMMUNOSUPPRESSIVE DRUG CYCLOSPORINE-A

Cyclophilin is a cellular receptor for the immunosuppressive drug cycl osporin A (CsA). Cyclophilin C (CyPC) is highly expressed in murine ki dney, making it a potential mediator of the nephrotoxic effects of CsA . The structure of murine CyPC complexed with CsA has been solved and refined to an R factor of 0.197 at a 1.64-angstrom resolution. Superpo sition of the CyPC-CsA structure with the unligated cyclophilin A (CyP A) revealed significant migration of three loops: Gln-179 to Thr-189, Asp-47 to Lys-49, and Met-170 to Ile-176. The proximity of the loop Gl n-179 to Thr-189 to the CsA binding site may account for the unique bi nding of a 77-kDa glycoprotein, CyPC binding protein (CyCAP), to CyPC. The binding of CsA to CyPC is similar to that of CsA to human T-cell cyclophilin A (CyPA). However, the conformation of CsA when bound to C yPC is significantly different from that when bound to CyPA. These dif ferences may reflect conformational variation of CsA when bound to dif ferent proteins. Alternatively, the previous CyPA-CsA structure at low resolution may not provide sufficient details for a comparison with t he CyPC-CsA structure.