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{{STRUCTURE_3ruu| PDB=3ruu | SCENE= }}  
==FXR with SRC1 and GSK237==
===FXR with SRC1 and GSK237===
<StructureSection load='3ruu' size='340' side='right' caption='[[3ruu]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
{{ABSTRACT_PUBMED_21890356}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[3ruu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RUU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3RUU FirstGlance]. <br>
==Disease==
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37G:6-(4-{[3-(2,6-DICHLOROPHENYL)-5-(PROPAN-2-YL)-1,2-OXAZOL-4-YL]METHOXY}PHENYL)-1H-INDOLE-3-CARBOXYLIC+ACID'>37G</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rut|3rut]], [[3rvf|3rvf]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BAR, FXR, HRR1, NR1H4, RIP14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ruu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ruu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ruu RCSB], [http://www.ebi.ac.uk/pdbsum/3ruu PDBsum]</span></td></tr>
</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.  
[[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 ==
[[http://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>  [[http://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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.


==Function==
Conformationally constrained farnesoid X receptor (FXR) agonists: Alternative replacements of the stilbene.,Akwabi-Ameyaw A, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB Bioorg Med Chem Lett. 2011 Aug 11. PMID:21890356<ref>PMID:21890356</ref>
[[http://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> [[http://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>  


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3ruu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3RUU OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:021890356</ref><references group="xtra"/><references/>
*[[Bile acid receptor|Bile acid receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Histone acetyltransferase]]
[[Category: Histone acetyltransferase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Madauss, K P.]]
[[Category: Madauss, K P]]
[[Category: Williams, S P.]]
[[Category: Williams, S P]]
[[Category: Alpha-helical sandwich]]
[[Category: Alpha-helical sandwich]]
[[Category: Bile acid]]
[[Category: Bile acid]]

Revision as of 13:50, 19 December 2014

FXR with SRC1 and GSK237FXR with SRC1 and GSK237

Structural highlights

3ruu is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:BAR, FXR, HRR1, NR1H4, RIP14 (Homo sapiens)
Activity:Histone acetyltransferase, with EC number 2.3.1.48
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[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

[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.[1] [2] [3] [4] [5] [6] [7] [8] [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.[9] [10] [11] [12] [13] [14] [15]

Publication Abstract from PubMed

To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.

Conformationally constrained farnesoid X receptor (FXR) agonists: Alternative replacements of the stilbene.,Akwabi-Ameyaw A, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB Bioorg Med Chem Lett. 2011 Aug 11. PMID:21890356[16]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B. Identification of a nuclear receptor for bile acids. Science. 1999 May 21;284(5418):1362-5. PMID:10334992
  2. ↑ Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999 May 21;284(5418):1365-8. PMID:10334993
  3. ↑ Holt JA, Luo G, Billin AN, Bisi J, McNeill YY, Kozarsky KF, Donahee M, Wang DY, Mansfield TA, Kliewer SA, Goodwin B, Jones SA. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 2003 Jul 1;17(13):1581-91. Epub 2003 Jun 18. PMID:12815072 doi:10.1101/gad.1083503
  4. ↑ Ananthanarayanan M, Li S, Balasubramaniyan N, Suchy FJ, Walsh MJ. Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1. J Biol Chem. 2004 Dec 24;279(52):54348-57. Epub 2004 Oct 6. PMID:15471871 doi:M410021200
  5. ↑ 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. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell. 2003 Apr;11(4):1079-92. PMID:12718892
  6. ↑ Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Jones SA, Kaldor I, Liu Y, Madauss KP, Marr HB, McFadyen RB, Miller AB, Iii FN, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4339-43. Epub 2008 Jun 28. PMID:18621523 doi:10.1016/j.bmcl.2008.06.073
  7. ↑ Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Parks DJ, Todd D, Williams SP, Wisely GB. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2969-73. Epub 2009 Apr 18. PMID:19410460 doi:10.1016/j.bmcl.2009.04.047
  8. ↑ Akwabi-Ameyaw A, Bass JY, Caldwell RD, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, McFadyen RB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Bruce Wisely G. FXR agonist activity of conformationally constrained analogs of GW 4064. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4733-9. Epub 2009 Jun 21. PMID:19586769 doi:10.1016/j.bmcl.2009.06.062
  9. ↑ Kalkhoven E, Valentine JE, Heery DM, Parker MG. Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 1998 Jan 2;17(1):232-43. PMID:9427757 doi:10.1093/emboj/17.1.232
  10. ↑ Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354-7. PMID:7481822
  11. ↑ Hayashi Y, Ohmori S, Ito T, Seo H. A splicing variant of Steroid Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. Biochem Biophys Res Commun. 1997 Jul 9;236(1):83-7. PMID:9223431 doi:10.1006/bbrc.1997.6911
  12. ↑ Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194-8. PMID:9296499 doi:10.1038/38304
  13. ↑ Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor induction of gene transcription: a two-step model. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7879-84. PMID:9223281
  14. ↑ Liu Z, Wong J, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9485-90. PMID:10449719
  15. ↑ Litterst CM, Kliem S, Marilley D, Pfitzner E. NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the FDL motif in the alpha-helical region of the STAT5 transactivation domain. J Biol Chem. 2003 Nov 14;278(46):45340-51. Epub 2003 Sep 3. PMID:12954634 doi:http://dx.doi.org/10.1074/jbc.M303644200
  16. ↑ Akwabi-Ameyaw A, Caravella JA, Chen L, Creech KL, Deaton DN, Madauss KP, Marr HB, Miller AB, Navas F 3rd, Parks DJ, Spearing PK, Todd D, Williams SP, Wisely GB. Conformationally constrained farnesoid X receptor (FXR) agonists: Alternative replacements of the stilbene. Bioorg Med Chem Lett. 2011 Aug 11. PMID:21890356 doi:10.1016/j.bmcl.2011.08.034

3ruu, resolution 2.50Å

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