Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies

被引:20
|
作者
Yang, Liping [1 ]
Broderick, David [1 ]
Campbell, Yan [4 ,6 ]
Gombart, Adrian F. [4 ]
Stevens, Jan F. [4 ,5 ]
Jiang, Yuan [3 ]
Hsu, Victor L. [6 ]
Bisson, William H. [2 ]
Maier, Claudia S. [1 ,4 ]
机构
[1] Oregon State Univ, Dept Chem, Corvallis, OR 97331 USA
[2] Oregon State Univ, Dept Environm & Mol Toxicol, Corvallis, OR 97331 USA
[3] Oregon State Univ, Dept Stat, Corvallis, OR 97331 USA
[4] Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA
[5] Oregon State Univ, Dept Pharmaceut Sci, Corvallis, OR 97331 USA
[6] Oregon State Univ, Dept Biochem & Biophys, Corvallis, OR 97331 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2016年 / 1864卷 / 12期
基金
美国国家卫生研究院;
关键词
Farnesoid X receptor; Prenylflavonoids; Hydrogen deuterium exchange; Mass spectrometry; Xanthohumol; Fluorescence spectroscopy; BOVINE SERUM-ALBUMIN; BILE-ACID; LIGAND-BINDING; THERAPEUTIC TARGET; NATURAL LIGANDS; PROTEIN; FXR; XANTHOHUMOL; ANTAGONIST; DYNAMICS;
D O I
10.1016/j.bbapap.2016.08.019
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (DC). 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. (C) 2016 Elsevier B.V. All rights reserved.
引用
收藏
页码:1667 / 1677
页数:11
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