title: Cyclosporin A-cyclophilin complex formation. A model based on X-ray and NMR data.
abstract: The previously determined 3D NMR solution structure of cyclophilin-bound cyclosporin A (CsA) was docked onto the X-ray crystal structure of cyclophilin. Intermolecular nuclear Overhauser effects (NOE) between CsA and cyclophilin were used as constraints in a restrained energy minimization to generate a model of the complex which satisfied all the NOE distance constraints. The model shows that the residues 9 to 11 and 1 to 5 of the cyclic CsA molecule are in contact with cyclophilin. Comparing the model of the CsA-cyclophilin complex to the X-ray crystal structure of a complex of cyclophilin with a substrate for peptidyl-proline cis-trans isomerase activity, i.e. the linear tetrapeptide substrate ac-Ala-Ala-Pro-Ala-amc (ac, acetyl; amc, amidomethylcoumarin), one notices that the contacting peptide segments in the two ligands are oriented in opposite directions, and that the side chain of MeVal-11 of CsA superposes rather precisely with the position of the prolyl residue in ac-Ala-Ala-Pro-Ala-amc.
authors.affiliation: Institut für Molekularbiologie und Biophysik, Eidgenössische Technische Hochschule-Hönggerberg, Zürich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Spitzfaden
authors.forename: H P
authors.initials: HP
authors.lastname: Weber
authors.forename: W
authors.initials: W
authors.lastname: Braun
authors.forename: J
authors.initials: J
authors.lastname: Kallen
authors.forename: G
authors.initials: G
authors.lastname: Wider
authors.forename: H
authors.initials: H
authors.lastname: Widmer
authors.forename: M D
authors.initials: MD
authors.lastname: Walkinshaw
authors.forename: K
authors.initials: K
authors.lastname: Wüthrich
mesh_terms: D000591:Amino Acid Isomerases / Q000737:chemistry*; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry*; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D002352:Carrier Proteins; D046911:Macromolecular Substances; D016572:Cyclosporine; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase