Thioxylated cyclosporin A for studying protein-drug interactions.
Single atom substitution of cyclosporin A (CsA) through thioxylation has been used to study the structure-activity relationship of the immunosuppressive complex, involving the CsA receptor protein cyclophilin 18 (Cyp18) and the immunological target protein phosphatase calcineurin (CaN), illustrating the contributions of peptide backbone in protein-drug interaction. Moreover, the subtle difference between thioxylation positions in CsA has led to a remarkable change in the quenching effect on Cyp18 intrinsic fluorescence. Using the thioxylated compound Cs7 as an isosteric derivative of CsA in competition assay, the experiment has led to the determination of koffvalue in solution. Whereas the conformational heterogeneity of CsA has been found to be associated with its two-phase binding kinetics to Cyp18, the dissociation rate of CsA from complex is independent from the initial ligand structure.
B CUBE Center for Molecular Bioengineering, Technical University Dresden, Arnoldstr. 18, 01307 Dresden, Germany.
Weilin
W
Lin
Institute for Pharmacy, Department of Pharmacology, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
Frank
F
Erdmann
B CUBE Center for Molecular Bioengineering, Technical University Dresden, Arnoldstr. 18, 01307 Dresden, Germany.
Andres
A
Quintero
Max-Planck-Institute for Biophysical Chemistry, Göttingen, BO Halle (Saale) Weinbergweg 22, 06120 Halle (Saale), Germany.
Gunter
G
Fischer
B CUBE Center for Molecular Bioengineering, Technical University Dresden, Arnoldstr. 18, 01307 Dresden, Germany. Electronic address: yixin.zhang@bcube-dresden.de.
Yixin
Y
Zhang
D019703:Calcineurin / Q000378:metabolism; D021983:Cyclophilins / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D011485:Protein Binding
D007166:Immunosuppressive Agents; C431607:cyclophilin 19; D016572:Cyclosporine; D019703:Calcineurin; D021983:Cyclophilins
Calcineurin; Cyclophilin 18; Cyclosporin A; Dissociation rate; Protein–drug interaction