TitleConformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies.
Publication TypeJournal Article
Year of Publication2016
AuthorsYang L, Broderick D, Campbell Y, Gombart AF, Stevens JF, Jiang Y, Hsu VL, Bisson WH, Maier CS
JournalBiochim Biophys Acta
Date Published2016 12
KeywordsCell Line, Tumor, Deuterium Exchange Measurement, Flavonoids, HEK293 Cells, Humans, Kinetics, Ligands, Mass Spectrometry, Molecular Docking Simulation, Molecular Dynamics Simulation, Propiophenones, Protein Conformation, Receptors, Cytoplasmic and Nuclear, Spectrometry, Fluorescence

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.

Alternate JournalBiochim. Biophys. Acta
PubMed ID27596062
PubMed Central IDPMC5071164
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
R01 AT009168 / AT / NCCIH NIH HHS / United States
S10 RR025628 / RR / NCRR NIH HHS / United States