Yang Liping, Broderick David, Campbell Yan, Gombart Adrian F, Stevens Jan F, Jiang Yuan, Hsu Victor L, Bisson William H, Maier Claudia S
Department of Chemistry, Oregon State University, Corvallis, OR 97331, USA.
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
Biochim Biophys Acta. 2016 Dec;1864(12):1667-1677. doi: 10.1016/j.bbapap.2016.08.019. Epub 2016 Sep 3.
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.
我们报道了法尼醇X受体（FXR）与异戊烯基黄酮类化合物之间的分子相互作用，异戊烯基黄酮类化合物是一类新兴的FXR调节剂。FXR是缓解代谢综合征（MetS）的一个有吸引力的治疗靶点，因为FXR可激活抑制性核受体小异源二聚体伴侣（SHP），从而抑制糖异生和从头脂肪生成。我们和其他人已经表明，啤酒花植物（Humulus lupulus L.）的主要异戊烯基黄酮类化合物黄腐酚（XN）是一种FXR激动剂，基于其在体内影响脂质和葡萄糖代谢以及在胆管癌细胞和HEK293细胞中诱导FXR靶基因的能力。然而，目前缺乏研究来阐明异戊烯基黄酮类化合物调节FXR的分子机制。我们解决了这一缺陷，并报告了关于FXR异戊烯基黄酮类化合物相互作用的首次系统研究。我们将氢氘交换质谱（HDX-MS）与计算研究相结合，以剖析异戊烯基黄酮类化合物相互作用对人FXR配体结合域（LBD）的分子识别和构象影响。测试了四种异戊烯基黄酮类化合物：黄腐酚、一种异戊烯基化查耳酮、两种异戊烯基化黄酮酮，即异黄腐酚（IX）和8-异戊烯基柚皮素（8PN），以及一种半合成异戊烯基黄酮类衍生物四氢黄腐酚（TX）。通过FXR异戊烯基黄酮类化合物复合物的计算机预测模型增强HDX保护谱数据，从而确定了异戊烯基黄酮类化合物在经典配体结合口袋内的相互作用。我们的研究结果为探索异戊烯基化查耳酮和黄酮酮的化学支架奠定了基础，这些支架可作为未来对这一重要核受体进行结构活性研究的先导，这可能与改善与肥胖和MetS相关的脂质代谢紊乱有关。
