Crystal structure of murine cyclophilin C complexed with immunosuppressive drug cyclosporin A.
Cyclophilin is a cellular receptor for the immunosuppressive drug cyclosporin A (CsA). Cyclophilin C (CyPC) is highly expressed in murine kidney, 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-A resolution. Superposition of the CyPC-CsA structure with the unligated cyclophilin A (CyPA) 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 Gln-179 to Thr-189 to the CsA binding site may account for the unique binding 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 CyPC is significantly different from that when bound to CyPA. These differences may reflect conformational variation of CsA when bound to different proteins. Alternatively, the previous CyPA-CsA structure at low resolution may not provide sufficient details for a comparison with the CyPC-CsA structure.
Ke
H
H
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599.
Zhao
Y
Y
Luo
F
F
Weissman
I
I
Friedman
J
J
D000591:Amino Acid Isomerases / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods; D000072622:Cyclophilin C; D021983:Cyclophilins; D016572:Cyclosporine / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism
D002352:Carrier Proteins; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D021983:Cyclophilins; D000072622:Cyclophilin C