3fxv

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Current revision (06:37, 3 April 2024) (edit) (undo)
 
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<StructureSection load='3fxv' size='340' side='right'caption='[[3fxv]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
<StructureSection load='3fxv' size='340' side='right'caption='[[3fxv]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3fxv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. 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>
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<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>
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</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>
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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]] 2.26&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1H4, hCG_20893 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=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'>[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>
<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>
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== Disease ==
 
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[[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 ==
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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> [[https://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</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>
== 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=3fxv 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=3fxv ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
 
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== Publication Abstract from PubMed ==
 
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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&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 3fxv" style="background-color:#fffaf0;"></div>
 
==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Benson, G M]]
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[[Category: Benson GM]]
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[[Category: Bleicher, K]]
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[[Category: Bleicher K]]
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[[Category: Chen, L]]
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[[Category: Chen L]]
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[[Category: Feng, S]]
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[[Category: Feng S]]
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[[Category: Grether, U]]
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[[Category: Grether U]]
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[[Category: He, Y]]
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[[Category: He Y]]
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[[Category: Hong, D]]
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[[Category: Hong D]]
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[[Category: Kuhn, B]]
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[[Category: Kuhn B]]
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[[Category: Martin, R]]
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[[Category: Martin R]]
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[[Category: Plancher, J M]]
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[[Category: Plancher J-M]]
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[[Category: Richter, H]]
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[[Category: Richter H]]
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[[Category: Rudolph, M G]]
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[[Category: Rudolph MG]]
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[[Category: Wang, Z]]
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[[Category: Wang Z]]
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[[Category: Yang, M]]
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[[Category: Yang M]]
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[[Category: Zhang, Z]]
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[[Category: Zhang Z]]
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[[Category: Activator]]
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[[Category: Acyltransferase]]
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[[Category: Alternative splicing]]
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[[Category: Bile acid]]
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[[Category: Cholesterol]]
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[[Category: Chromosomal rearrangement]]
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[[Category: Dna-binding]]
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[[Category: Hormone receptor]]
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[[Category: Metal-binding]]
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[[Category: Nuclear receptor]]
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[[Category: Nucleus]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Proto-oncogene]]
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[[Category: Receptor]]
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[[Category: Transcription]]
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[[Category: Transcription regulation]]
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[[Category: Transferase]]
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[[Category: Ubl conjugation]]
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[[Category: Zinc]]
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[[Category: Zinc-finger]]
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Current revision

Identification of an N-oxide pyridine GW4064 analogue as a potent FXR agonist

PDB ID 3fxv

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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