1osh
From Proteopedia
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==A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR== | ==A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR== | ||
| - | <StructureSection load='1osh' size='340' side='right' caption='[[1osh]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='1osh' size='340' side='right'caption='[[1osh]], [[Resolution|resolution]] 1.80Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[1osh]] is a 1 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[1osh]] is a 1 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=1OSH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1OSH FirstGlance]. <br> |
| - | </td></tr><tr id=' | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id=' | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FEX:METHYL+3-{3-[(CYCLOHEXYLCARBONYL){[4-(DIMETHYLAMINO)BIPHENYL-4-YL]METHYL}AMINO]PHENYL}ACRYLATE'>FEX</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1osh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1osh OCA], [https://pdbe.org/1osh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1osh RCSB], [https://www.ebi.ac.uk/pdbsum/1osh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1osh ProSAT]</span></td></tr> |
</table> | </table> | ||
== 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> |
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/os/1osh_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/os/1osh_consurf.spt"</scriptWhenChecked> |
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1osh ConSurf]. |
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | The farnesoid X receptor (FXR) functions as a bile acid (BA) sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. However, BAs are poor reagents for characterizing FXR functions due to multiple receptor independent properties. Accordingly, using combinatorial chemistry we evolved a small molecule agonist termed fexaramine with 100-fold increased affinity relative to natural compounds. Gene-profiling experiments conducted in hepatocytes with FXR-specific fexaramine versus the primary BA chenodeoxycholic acid (CDCA) produced remarkably distinct genomic targets. Highly diffracting cocrystals (1.78 A) of fexaramine bound to the ligand binding domain of FXR revealed the agonist sequestered in a 726 A(3) hydrophobic cavity and suggest a mechanistic basis for the initial step in the BA signaling pathway. The discovery of fexaramine will allow us to unravel the FXR genetic network from the BA network and selectively manipulate components of the cholesterol pathway that may be useful in treating cholesterol-related human diseases. | ||
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| - | A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.,Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast-Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, Rosenfeld JM, Alvarez JG, Noel JP, Nicolaou KC, Evans RM Mol Cell. 2003 Apr;11(4):1079-92. PMID:12718892<ref>PMID:12718892</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 1osh" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
| - | *[[Bile acid receptor|Bile acid receptor]] | + | *[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]] |
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: Alvarez | + | [[Category: Large Structures]] |
| - | [[Category: Anisfeld | + | [[Category: Alvarez JGA]] |
| - | [[Category: Bowman | + | [[Category: Anisfeld AM]] |
| - | [[Category: Downes | + | [[Category: Bowman ME]] |
| - | [[Category: Edwards | + | [[Category: Downes M]] |
| - | [[Category: Evans | + | [[Category: Edwards PA]] |
| - | [[Category: Ferrer | + | [[Category: Evans RM]] |
| - | [[Category: Hogenesch | + | [[Category: Ferrer J-L]] |
| - | [[Category: Hughes | + | [[Category: Hogenesch JB]] |
| - | [[Category: Kast-Woelbern | + | [[Category: Hughes R]] |
| - | [[Category: Nicolaou | + | [[Category: Kast-Woelbern HR]] |
| - | [[Category: Noel | + | [[Category: Nicolaou KC]] |
| - | [[Category: Roecker | + | [[Category: Noel JP]] |
| - | [[Category: Rosenfeld | + | [[Category: Roecker AJ]] |
| - | [[Category: Verdecia | + | [[Category: Rosenfeld JM]] |
| - | + | [[Category: Verdecia MA]] | |
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| - | + | ||
Current revision
A Chemical, Genetic, and Structural Analysis of the nuclear bile acid receptor FXR
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Categories: Homo sapiens | Large Structures | Alvarez JGA | Anisfeld AM | Bowman ME | Downes M | Edwards PA | Evans RM | Ferrer J-L | Hogenesch JB | Hughes R | Kast-Woelbern HR | Nicolaou KC | Noel JP | Roecker AJ | Rosenfeld JM | Verdecia MA
