3l1b
From Proteopedia
(Difference between revisions)
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==Complex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound== | ==Complex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound== | ||
| - | <StructureSection load='3l1b' size='340' side='right' caption='[[3l1b]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='3l1b' size='340' side='right'caption='[[3l1b]], [[Resolution|resolution]] 1.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[3l1b]] is a 1 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[3l1b]] 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=3L1B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3L1B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=635:1-METHYLETHYL+8-FLUORO-1,1-DIMETHYL-3-{[4-(3-MORPHOLIN-4-YLPROPOXY)PHENYL]CARBONYL}-1,2,3,6-TETRAHYDROAZEPINO[4,5-B]INDOLE-5-CARBOXYLATE'>635</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=635:1-METHYLETHYL+8-FLUORO-1,1-DIMETHYL-3-{[4-(3-MORPHOLIN-4-YLPROPOXY)PHENYL]CARBONYL}-1,2,3,6-TETRAHYDROAZEPINO[4,5-B]INDOLE-5-CARBOXYLATE'>635</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=3l1b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3l1b OCA], [https://pdbe.org/3l1b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3l1b RCSB], [https://www.ebi.ac.uk/pdbsum/3l1b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3l1b ProSAT]</span></td></tr> | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | |
</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]] | ||
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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=3l1b 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=3l1b ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering. | ||
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| - | Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates.,Lundquist JT, Harnish DC, Kim CY, Mehlmann JF, Unwalla RJ, Phipps KM, Crawley ML, Commons T, Green DM, Xu W, Hum WT, Eta JE, Feingold I, Patel V, Evans MJ, Lai K, Borges-Marcucci L, Mahaney PE, Wrobel JE J Med Chem. 2010 Feb 25;53(4):1774-87. PMID:20095622<ref>PMID:20095622</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 3l1b" 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: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Lundquist JT]] |
| - | [[Category: | + | [[Category: Xu W]] |
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Current revision
Complex Structure of FXR Ligand-binding domain with a tetrahydroazepinoindole compound
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