3dr1: Difference between revisions

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{{STRUCTURE_3dr1|  PDB=3dr1  |  SCENE=  }}
===Side-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptor===
{{ABSTRACT_PUBMED_18940664}}


==Disease==
==Side-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptor==
[[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.  
<StructureSection load='3dr1' size='340' side='right'caption='[[3dr1]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3dr1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DR1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3DR1 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5D:(1R,3R)-5-[(2E)-3-{(1S,3R)-2,2,3-TRIMETHYL-3-[6,6,6-TRIFLUORO-5-HYDROXY-5-(TRIFLUOROMETHYL)HEX-3-YN-1-YL]CYCLOPENTYL}PROP-2-EN-1-YLIDENE]CYCLOHEXANE-1,3-DIOL'>C5D</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=3dr1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3dr1 OCA], [https://pdbe.org/3dr1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3dr1 RCSB], [https://www.ebi.ac.uk/pdbsum/3dr1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3dr1 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/VDRA_DANRE VDRA_DANRE] Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.<ref>PMID:17218092</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/dr/3dr1_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </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/main_output.php?pdb_ID=3dr1 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.


==Function==
Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.,Eelen G, Valle N, Sato Y, Rochel N, Verlinden L, De Clercq P, Moras D, Bouillon R, Munoz A, Verstuyf A Chem Biol. 2008 Oct 20;15(10):1029-34. PMID:18940664<ref>PMID:18940664</ref>
[[http://www.uniprot.org/uniprot/VDRA_DANRE VDRA_DANRE]] Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.<ref>PMID:17218092</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>
[[3dr1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3DR1 OCA].
</div>
 
<div class="pdbe-citations 3dr1" style="background-color:#fffaf0;"></div>
==Reference==
== References ==
<ref group="xtra">PMID:018940664</ref><references group="xtra"/><references/>
<references/>
__TOC__
</StructureSection>
[[Category: Danio rerio]]
[[Category: Danio rerio]]
[[Category: Histone acetyltransferase]]
[[Category: Homo sapiens]]
[[Category: Moras, D.]]
[[Category: Large Structures]]
[[Category: Rochel, N.]]
[[Category: Moras D]]
[[Category: Sato, Y.]]
[[Category: Rochel N]]
[[Category: Activator]]
[[Category: Sato Y]]
[[Category: Acyltransferase]]
[[Category: Dna-binding]]
[[Category: Gene regulation]]
[[Category: Gene regulation-transferase complex]]
[[Category: Metal-binding]]
[[Category: Nucleus]]
[[Category: Phosphoprotein]]
[[Category: Proto-oncogene]]
[[Category: Receptor]]
[[Category: Transcription]]
[[Category: Transcription regulation]]
[[Category: Transferase]]
[[Category: Zinc-finger]]

Latest revision as of 18:13, 1 November 2023

Side-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptorSide-chain fluorine atoms of non-steroidal vitamin D3 analogs stabilize helix 12 of vitamin D receptor

Structural highlights

3dr1 is a 2 chain structure with sequence from Danio rerio and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Side chain fluorination is often used to make analogs of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] resistant to degradation by 24-hydroxylase. The fluorinated nonsteroidal analogs CD578, WU515, and WY1113 have an increased prodifferentiating action on SW480-ADH colon cancer cells, which correlated with stronger induction of vitamin D receptor (VDR)-coactivator interactions and stronger repression of beta-catenin/TCF activity. Cocrystallization of analog CD578 with the zebrafish (z)VDR and an SRC-1 coactivator peptide showed that the fluorine atoms of CD578 make additional contacts with Val444 and Phe448 of activation helix 12 (H12) of the zVDR and with Leu440 of the H11-H12 loop. Consequently, the SRC-1 peptide makes more contacts with the VDR-CD578 complex than with the VDR-1,25(OH)2D3 complex. These data show that fluorination not only affects degradation of an analog but can also have direct effects on H12 stabilization.

Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor.,Eelen G, Valle N, Sato Y, Rochel N, Verlinden L, De Clercq P, Moras D, Bouillon R, Munoz A, Verstuyf A Chem Biol. 2008 Oct 20;15(10):1029-34. PMID:18940664[2]

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

References

  1. ↑ Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003
  2. ↑ Eelen G, Valle N, Sato Y, Rochel N, Verlinden L, De Clercq P, Moras D, Bouillon R, Munoz A, Verstuyf A. Superagonistic fluorinated vitamin D3 analogs stabilize helix 12 of the vitamin D receptor. Chem Biol. 2008 Oct 20;15(10):1029-34. PMID:18940664 doi:10.1016/j.chembiol.2008.08.008

3dr1, resolution 2.70Å

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