3bej
From Proteopedia
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<StructureSection load='3bej' size='340' side='right'caption='[[3bej]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='3bej' size='340' side='right'caption='[[3bej]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[3bej]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/ | + | <table><tr><td colspan='2'>[[3bej]] 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=3BEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BEJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MUF:(8ALPHA,10ALPHA,13ALPHA,17BETA)-17-[(4-HYDROXYPHENYL)CARBONYL]ANDROSTA-3,5-DIENE-3-CARBOXYLIC+ACID'>MUF</scene>, <scene name='pdbligand=YT3:YTTRIUM+(III)+ION'>YT3</scene> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MUF:(8ALPHA,10ALPHA,13ALPHA,17BETA)-17-[(4-HYDROXYPHENYL)CARBONYL]ANDROSTA-3,5-DIENE-3-CARBOXYLIC+ACID'>MUF</scene>, <scene name='pdbligand=YT3:YTTRIUM+(III)+ION'>YT3</scene></td></tr> | |
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bej OCA], [https://pdbe.org/3bej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bej RCSB], [https://www.ebi.ac.uk/pdbsum/3bej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bej ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bej OCA], [https://pdbe.org/3bej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bej RCSB], [https://www.ebi.ac.uk/pdbsum/3bej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bej ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == Disease == | ||
| - | [[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. | ||
== 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]] | ||
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</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=3bej ConSurf]. | </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=3bej 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), 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 in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-A resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor. | ||
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| - | Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation.,Soisson SM, Parthasarathy G, Adams AD, Sahoo S, Sitlani A, Sparrow C, Cui J, Becker JW Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5337-42. Epub 2008 Apr 7. PMID:18391212<ref>PMID:18391212</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 3bej" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Becker | + | [[Category: Becker JW]] |
| - | [[Category: Parthasarathy | + | [[Category: Parthasarathy G]] |
| - | [[Category: Soisson | + | [[Category: Soisson SM]] |
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Current revision
Structure of human FXR in complex with MFA-1 and co-activator peptide
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