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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies
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Conformational modulation of the farnesoid X receptor by prenylflavonoids: Insights from hydrogen deuterium exchange mass spectrometry (HDX-MS), fluorescence titration and molecular docking studies

机译：异戊二烯类黄酮对法尼醇X受体的构象调节：氢氘交换质谱（HDX-MS），荧光滴定和分子对接研究的见解

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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.
机译：我们报告了法尼醇X受体（FXR）与异戊二烯类黄酮（一种新兴的FXR调节剂）的分子相互作用。 FXR是缓解代谢综合症（MetS）的有吸引力的治疗靶标，因为FXR激活抑制性核受体，小异二聚体伴侣（SHP），从而抑制糖异生和新生脂肪形成。我们和其他人已表明，啤酒花植物（Hu草）的主要异戊二烯类黄酮黄腐酚（XN）是FXR激动剂，因为它具有影响体内脂质和葡萄糖代谢并在胆道癌细胞中诱导FXR靶基因的能力。和HEK293细胞。但是，目前尚缺乏合理的研究来合理化异戊二烯类黄酮对FXR调节的分子机制。我们解决了这一缺陷，并报告了FXR异戊二烯类黄酮相互作用的第一个系统研究。我们将氢氘交换质谱（HDX-MS）与计算研究相结合，以分析异戊二烯类黄酮相互作用对人FXR配体结合域（LBD）的分子识别和构象影响。测试了四个异戊烯类黄酮：黄腐酚，异戊烯化查尔酮，两个异戊烯化黄酮，即异黄腐酚（IX）和8-异戊烯基柚皮苷（8PN），以及半合成异戊烯类黄酮衍生物四氢黄腐酚（DC）。 FXR异戊二烯类黄酮复合物的计算机预测模型对HDX保护特性数据的增强导致了规范配体结合口袋中异戊二烯类黄酮相互作用的映射。我们的发现为探索烯丙基化查耳酮和黄烷酮的化学支架奠定了基础，可作为对该重要核受体进行未来结构活性研究的线索，与减轻与肥胖症和MetS相关的脂质代谢紊乱有关。 （C）2016 Elsevier B.V.保留所有权利。

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