Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies
| Autor: | William H. Bisson, Victor L. Hsu, Claudia S. Maier, Adrian F. Gombart, Liping Yang, Yan Campbell, Jan F. Stevens, Yuan Jiang, David Broderick |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Protein Conformation Biophysics Receptors Cytoplasmic and Nuclear Molecular Dynamics Simulation Ligands Biochemistry Mass Spectrometry Article Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Molecular recognition Prenylation Cell Line Tumor Humans Molecular Biology Flavonoids Propiophenones Isoxanthohumol Chemistry Deuterium Exchange Measurement Prenylflavonoid Molecular Docking Simulation Kinetics 030104 developmental biology HEK293 Cells Spectrometry Fluorescence Nuclear receptor 030220 oncology & carcinogenesis Xanthohumol Small heterodimer partner Farnesoid X receptor |
| Zdroj: | Biochimica et biophysica acta. 1864(12) |
| ISSN: | 0006-3002 |
| Popis: | We report on the molecular interactions of the farnesoid X receptor (FXR) with prenylflavonoids, an emerging class of FXR modulators. FXR is an attractive therapeutic target for mitigating metabolic syndromes (MetS) because FXR activates the inhibitory nuclear receptor, small heterodimer partner (SHP), thereby inhibiting both gluconeogenesis and de novo lipogenesis. We and others have shown that xanthohumol (XN), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), is a FXR agonist based on its ability to affect lipid and glucose metabolism in vivo and to induces FXR target genes in biliary carcinoma cells and HEK293 cells. However, studies are currently lacking to rationalize the molecular mechanisms of FXR modulation by prenylflavonoids. We addressed this deficiency and report the first systematic study of FXR prenylflavonoid interactions. We combined hydrogen deuterium exchange mass spectrometry (HDX-MS) with computational studies for dissecting molecular recognition and conformational impact of prenylflavonoid interactions on the ligand binding domain (LBD) of human FXR. Four prenylflavonoids were tested: xanthohumol, a prenylated chalcone, two prenylated flavonones, namely isoxanthohumol (IX) and 8-prenylnaringenin (8PN), and a semisynthetic prenylflavonoid derivative, tetrahydroxanthohumol (TX). Enhancement of the HDX protection profile data by in silico predicted models of FXR prenylflavonoid complexes resulted in mapping of the prenylflavonoid interactions within the canonical ligand binding pocket. Our findings provide a foundation for the exploration of the chemical scaffolds of prenylated chalcones and flavanones as leads for future structure activity studies of this important nuclear receptor with potential relevance for ameliorating lipid metabolic disorders associated with obesity and MetS. |
| Databáze: | OpenAIRE |
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