2008
DOI: 10.1073/pnas.0710981105
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Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Abstract: The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand… Show more

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Cited by 82 publications
(67 citation statements)
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“…Surprisingly, different gene profi les are induced by fexaramine, CDCA, or GW4064 in mouse hepatocytes ( 122 ). The conformation of the ligand-receptor complex of FXR with fexaramine differs from that with CDCA or MFA-1, a synthetic steroidal FXR agonist ( 122,123 ), which might be linked to the differential induction of target genes by the respective ligands (SBARM concept).…”
Section: Fxr Agonistsmentioning
confidence: 99%
See 1 more Smart Citation
“…Surprisingly, different gene profi les are induced by fexaramine, CDCA, or GW4064 in mouse hepatocytes ( 122 ). The conformation of the ligand-receptor complex of FXR with fexaramine differs from that with CDCA or MFA-1, a synthetic steroidal FXR agonist ( 122,123 ), which might be linked to the differential induction of target genes by the respective ligands (SBARM concept).…”
Section: Fxr Agonistsmentioning
confidence: 99%
“…Structurally different ligands can bind differently to the FXR ligand binding pocket, whose intrinsic plasticity is defi ned by two cavities that can fi t ligand substructures ( 130,131 ). Depending on the (stereo)chemical properties of the ligand, the exact site of binding, the closeness of the ligand-receptor conformation, and the strength of the binding can differ ( 122,123,131 ). The specifi c ligand-receptor conformation can determine the ability of coregulators to act (i.e., activators to bind or repressors to dissociate), which defi nes the gene selectivity of a given ligand.…”
Section: Selective Bile Acid Receptor Modulatorsmentioning
confidence: 99%
“…In summary, NCOA binding molecules include many kinds of nuclear receptors, including androgen receptor, estrogen receptor, nuclear receptor subfamily 1, group I member 3 (NR1I3/CAR), bile acid receptor, and pregnane X receptor. [57][58][59][60][61] Other detailed investigation into the MoRFs with similar-fold partners was performed and discussed in our previous work. 52 …”
Section: Morf Sets With Partner Pairs Exhibiting Similar Foldsmentioning
confidence: 99%
“…To date increasing numbers of FXR␣ agonists have been discovered, such as GW4064, fexaramine, 6a-ethyl-CDCA, MFA-1, XL335, and ivermectin (7)(8)(9)(10)(11)(12). However, it was determined that FXR␣ activation by full agonist may also cause undesired side effects in animals.…”
mentioning
confidence: 99%