5iaw

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==Novel natural FXR modulator with a unique binding mode==
==Novel natural FXR modulator with a unique binding mode==
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<StructureSection load='5iaw' size='340' side='right' caption='[[5iaw]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
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<StructureSection load='5iaw' size='340' side='right'caption='[[5iaw]], [[Resolution|resolution]] 2.58&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5iaw]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IAW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IAW FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5iaw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IAW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IAW FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=T73:(1S,2R,4S)-1,7,7-TRIMETHYLBICYCLO[2.2.1]HEPTAN-2-YL+4-HYDROXYBENZOATE'>T73</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.58&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5iaw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iaw OCA], [http://pdbe.org/5iaw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iaw RCSB], [http://www.ebi.ac.uk/pdbsum/5iaw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5iaw ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=T73:(1S,2R,4S)-1,7,7-TRIMETHYLBICYCLO[2.2.1]HEPTAN-2-YL+4-HYDROXYBENZOATE'>T73</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5iaw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iaw OCA], [https://pdbe.org/5iaw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5iaw RCSB], [https://www.ebi.ac.uk/pdbsum/5iaw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5iaw ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://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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[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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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>
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==See Also==
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*[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5iaw" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Li, Y]]
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[[Category: Homo sapiens]]
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[[Category: Lu, Y]]
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[[Category: Large Structures]]
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[[Category: Nuclear protein receptor]]
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[[Category: Li Y]]
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[[Category: Transcription]]
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[[Category: Lu Y]]

Current revision

Novel natural FXR modulator with a unique binding mode

PDB ID 5iaw

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