Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies.
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.
Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA.
Liping
L
Yang
Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA.
David
D
Broderick
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Yan
Y
Campbell
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Adrian F
AF
Gombart
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR 97331, USA.
Jan F
JF
Stevens
Department of Statistics, Oregon State University, Corvallis, OR 97331, USA.
Yuan
Y
Jiang
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Victor L
VL
Hsu
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA.
William H
WH
Bisson
Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA; Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Electronic address: Claudia.maier@oregonstate.edu.
Claudia S
CS
Maier
D045744:Cell Line, Tumor; D041961:Deuterium Exchange Measurement; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D013058:Mass Spectrometry; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011427:Propiophenones / Q000378:metabolism; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D000099150:Receptor, Farnesoid X-Activated
D005419:Flavonoids; D008024:Ligands; D011427:Propiophenones; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C104536:xanthohumol
Farnesoid X receptor; Fluorescence spectroscopy; Hydrogen deuterium exchange; Mass spectrometry; Prenylflavonoids; Xanthohumol