3fxv
From Proteopedia
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==Identification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist== | ==Identification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist== | ||
| - | <StructureSection load='3fxv' size='340' side='right' caption='[[3fxv]], [[Resolution|resolution]] 2.26Å' scene=''> | + | <StructureSection load='3fxv' size='340' side='right'caption='[[3fxv]], [[Resolution|resolution]] 2.26Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[3fxv]] is a 2 chain structure with sequence from [ | + | <table><tr><td colspan='2'>[[3fxv]] is a 2 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=3FXV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FXV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=643:6-(4-{[3-(3,5-DICHLOROPYRIDIN-4-YL)-5-(1-METHYLETHYL)ISOXAZOL-4-YL]METHOXY}-2-METHYLPHENYL)-1-METHYL-1H-INDOLE-3-CARBOXYLIC+ACID'>643</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]] 2.26Å</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=643:6-(4-{[3-(3,5-DICHLOROPYRIDIN-4-YL)-5-(1-METHYLETHYL)ISOXAZOL-4-YL]METHOXY}-2-METHYLPHENYL)-1-METHYL-1H-INDOLE-3-CARBOXYLIC+ACID'>643</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=3fxv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fxv OCA], [https://pdbe.org/3fxv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fxv RCSB], [https://www.ebi.ac.uk/pdbsum/3fxv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fxv ProSAT]</span></td></tr> |
</table> | </table> | ||
| - | == Disease == | ||
| - | [[http://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]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fx/3fxv_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fx/3fxv_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=3fxv ConSurf]. |
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved. | ||
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| - | Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist.,Feng S, Yang M, Zhang Z, Wang Z, Hong D, Richter H, Benson GM, Bleicher K, Grether U, Martin RE, Plancher JM, Kuhn B, Rudolph MG, Chen L Bioorg Med Chem Lett. 2009 May 1;19(9):2595-8. Epub 2009 Mar 9. PMID:19328688<ref>PMID:19328688</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </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/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: Benson | + | [[Category: Large Structures]] |
| - | [[Category: Bleicher | + | [[Category: Benson GM]] |
| - | [[Category: Chen | + | [[Category: Bleicher K]] |
| - | [[Category: Feng | + | [[Category: Chen L]] |
| - | [[Category: Grether | + | [[Category: Feng S]] |
| - | [[Category: He | + | [[Category: Grether U]] |
| - | [[Category: Hong | + | [[Category: He Y]] |
| - | [[Category: Kuhn | + | [[Category: Hong D]] |
| - | [[Category: Martin | + | [[Category: Kuhn B]] |
| - | [[Category: Plancher | + | [[Category: Martin R]] |
| - | [[Category: Richter | + | [[Category: Plancher J-M]] |
| - | [[Category: Rudolph | + | [[Category: Richter H]] |
| - | [[Category: Wang | + | [[Category: Rudolph MG]] |
| - | [[Category: Yang | + | [[Category: Wang Z]] |
| - | [[Category: Zhang | + | [[Category: Yang M]] |
| - | + | [[Category: Zhang Z]] | |
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Current revision
Identification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist
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Categories: Homo sapiens | Large Structures | Benson GM | Bleicher K | Chen L | Feng S | Grether U | He Y | Hong D | Kuhn B | Martin R | Plancher J-M | Richter H | Rudolph MG | Wang Z | Yang M | Zhang Z
