title: Conformational Heterogeneity of Cyclosporin A in Cyclophilin 18 Binding.
abstract: The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of kon value (8.34 ± 0.22 x106 M-1s-1) in solution. Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition.
authors.affiliation: B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstrasse 18, 01307 Dresden, Germany.
authors.forename: Weilin
authors.initials: W
authors.lastname: Lin
authors.affiliation: B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstrasse 18, 01307 Dresden, Germany.
authors.forename: Andres
authors.initials: A
authors.lastname: Quintero
authors.affiliation: B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Arnoldstrasse 18, 01307 Dresden, Germany.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D021983:Cyclophilins / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D046911:Macromolecular Substances; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D012997:Solvents; D013050:Spectrometry, Fluorescence
chemical_list: D007166:Immunosuppressive Agents; D008024:Ligands; D046911:Macromolecular Substances; D012997:Solvents; D016572:Cyclosporine; D021983:Cyclophilins