title: The new immunosuppressant, isogarcinol, binds directly to its target enzyme calcineurin, unlike cyclosporin A and tacrolimus.
abstract: Isogarcinol, a bioactive polyisoprenylated benzophenone derivative isolated from Garcinia mangostana L., has been shown previously to exert a strong inhibitory effect on calcineurin and is thus a potential oral, low-toxicity immunomodulatory drug. In the present study, enzyme kinetic analysis showed that inhibition of calcineurin by isogarcinol was competitive. Fluorescence spectroscopy indicated that isogarcinol bound to calcineurin. Isothermal titration calorimetry showed that binding was mainly driven by enthalpy, and was exothermic because the enthalpy change exceeded the entropy reduction. The interaction force is either hydrogen bonding or Van der Waals forces. Fluorescence resonance energy transfer and molecular docking experiments indicated that there were two potential binding sites for isogarcinol in the catalytic domain of calcineurin. In summary, isogarcinol binds directly to calcineurin in vitro, unlike the classical calcineurin inhibitors cyclosporin A and tacrolimus.
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China; Key Laboratory of Protection and Development Utilization of Tropical Crop Germplasm Resources, Ministry of Education, College of Landscape and Horticulture, Hainan University, Haikou 570228, China.
authors.forename: Juren
authors.initials: J
authors.lastname: Cen
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: luo
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China.
authors.forename: Yadan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology, Beijing Key Laboratory, Beijing 100875, PR China. Electronic address: weiq@bnu.edu.cn.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
mesh_terms: D001577:Benzophenones / Q000737:chemistry; D019703:Calcineurin / Q000737:chemistry*; D016572:Cyclosporine / Q000737:chemistry*; D029760:Garcinia / Q000737:chemistry*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry* / Q000302:isolation & purification*; D011485:Protein Binding; D016559:Tacrolimus / Q000737:chemistry*
chemical_list: D001577:Benzophenones; D007166:Immunosuppressive Agents; C047723:benzophenone; D016572:Cyclosporine; D019703:Calcineurin; D016559:Tacrolimus
keywords: Calcineurin; Docking; Fluorescence spectroscopy; Isogarcinol; Isothermal titration calorimetry