Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone.
Conformational dynamics of human FXR-LBD ligand interactions studied by hydrogen/deuterium exchange mass spectrometry: insights into the antagonism of the hypolipidemic agent Z-guggulsterone.
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DOI：
10.1016/j.bbapap.2014.06.007
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发表时间：
2014-09
影响因子：
3.2
通讯作者：
Maier, Claudia S.
中科院分区：
文献类型：
--
作者：
Yang, Liping;Broderick, David;Jiang, Yuan;Hsu, Victor;Maier, Claudia S.
关键词：
法尼醇X受体（Farnesoid X Receptor，FXR）是核受体超家族的一员，在胆汁酸、脂类和葡萄糖代谢的调节中起着关键作用。FXR的调节功能由配体结合后配体结合结构域（LBD）的构象变化决定。虽然FXR是一个高度研究的潜在治疗靶点，但只有有限数量的FXR-激动剂复合物已成功结晶并随后产生高分辨率结构。目前尚无任何FXR拮抗剂复合物的结构信息。因此，我们探索了使用酰胺氢/氘交换（HDX）与质谱联用来表征配体结合后FXR-LBD的构象变化。获得了三种FXR配体化学型的配体特异性氘掺入曲线：GW 4064，一种合成的非甾体高亲和力激动剂;胆汁酸鹅去氧胆酸（CDCA），FXR的内源性低亲和力激动剂;和Z-guggulsterone（GG），一种甾体化学型的体外拮抗剂。比较其配体结合的FXR-LBD复合物的HDX谱揭示了GG的独特相互作用模式。讨论了FXR-LBD-拮抗剂相互作用的构象特征。
Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of transcription factors that plays a key role in the regulation of bile acids, lipid and glucose metabolisms. The regulative function of FXR is governed by conformational changes of the ligand binding domain (LBD) upon ligand binding. Although FXR is a highly researched potential therapeutic target, only a limited number of FXR-agonist complexes have been successfully crystallized and subsequently yielded high resolution structures. There is currently no structural information of any FXR-antagonist complexes publically available. We therefore explored the use of amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing conformational changes in the FXR-LBD upon ligand binding. Ligand-specific deuterium incorporation profiles were obtained for three FXR ligand chemotypes: GW4064, a synthetic non-steroidal high affinity agonist; the bile acid chenodeoxycholic acid (CDCA), the endogenous low affinity agonist of FXR; and Z-guggulsterone (GG), an in vitro antagonist of the steroid chemotype. Comparison of the HDX profiles of their ligand-bound FXR-LBD complexes revealed a unique mode of interaction for GG. The conformational features of the FXR-LBD-antagonist interaction are discussed.
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