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
作者： Liping Yang , David Broderick , Yuan Jiang , Victor Hsu , Claudia S. Maier
DOI: 10.1016/J.BBAPAP.2014.06.007
关键词:
摘要: Farnesoid X receptor (FXR) is a member of the nuclear superfamily transcription factors that plays key role in regulation bile acids, lipid and glucose metabolisms. The regulative function FXR governed by conformational changes ligand binding domain (LBD) upon binding. Although highly researched potential therapeutic target, only limited number FXR-agonist complexes have been successfully crystallized subsequently yielded high resolution structures. There currently no structural information any FXR-antagonist publically available. We therefore explored use amide hydrogen/deuterium exchange (HDX) coupled with mass spectrometry for characterizing FXR-LBD Ligand-specific deuterium incorporation profiles were obtained three chemotypes: GW4064, synthetic non-steroidal affinity agonist; acid chenodeoxycholic (CDCA), endogenous low agonist FXR; Z-guggulsterone (GG), an vitro antagonist steroid chemotype. A comparison HDX their ligand-bound revealed unique mode interaction GG. features FXR-LBD-antagonist are discussed.
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