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== Function ==
== Function ==
[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>  
[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>  
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== Publication Abstract from PubMed ==
Farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce the conformational change of FXR that modulates its binding to coregulators, resulting in distinctive functional profiles of FXR. However, the mechanisms for selectively recruiting coregulators by FXR remain elusive, partly due to the lack of FXR selective modulators. We report here the identification of two natural terpenoids, tschimgine and feroline, as a novel class of FXR modulators. Remarkably, crystal structures uncover a secondary binding-induced pocket important for ligand binding. Further, tschimgine or feroline induces dynamic conformational changes in the activation function 2 (AF-2) surface, leading to differential coregulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique for specific coregulators. Our findings thus provide a novel structure template and optimization basis for FXR selective modulators with clinical values.
A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Coregulator Assembly.,Zheng W, Lu Y, Lin S, Wang R, Qiu L, Zhu Y, Yao B, Guo F, Jin S, Jin L, Li Y Chembiochem. 2017 Feb 10. doi: 10.1002/cbic.201700059. PMID:28186695<ref>PMID:28186695</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
==See Also==

Latest revision as of 09:16, 20 March 2024

A unique binding model of FXR LBD with feroline

5ick, resolution 2.47Å

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