3wt6: Difference between revisions

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==A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl group==
==A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl group==
<StructureSection load='3wt6' size='340' side='right' caption='[[3wt6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
<StructureSection load='3wt6' size='340' side='right'caption='[[3wt6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3wt6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WT6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WT6 FirstGlance]. <br>
<table><tr><td colspan='2'>[[3wt6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WT6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WT6 FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=YA1:(1R,3R,7E,17BETA)-17-[(2R,3R)-3-BUTYL-6-HYDROXY-6-METHYLHEPTAN-2-YL]-2-METHYLIDENE-9,10-SECOESTRA-5,7-DIENE-1,3-DIOL'>YA1</scene><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&#8491;</td></tr>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wt5|3wt5]], [[3wt7|3wt7]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YA1:(1R,3R,7E,17BETA)-17-[(2R,3R)-3-BUTYL-6-HYDROXY-6-METHYLHEPTAN-2-YL]-2-METHYLIDENE-9,10-SECOESTRA-5,7-DIENE-1,3-DIOL'>YA1</scene></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3wt6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wt6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wt6 RCSB], [http://www.ebi.ac.uk/pdbsum/3wt6 PDBsum]</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=3wt6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wt6 OCA], [https://pdbe.org/3wt6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wt6 RCSB], [https://www.ebi.ac.uk/pdbsum/3wt6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wt6 ProSAT]</span></td></tr>
<table>
</table>
<div style="background-color:#fffaf0;">
== Function ==
== Publication Abstract from PubMed ==
[https://www.uniprot.org/uniprot/VDR_RAT VDR_RAT] 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. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.<ref>PMID:17227670</ref>  
We are continuing to study the structural basis of vitamin D receptor (VDR) agonism and antagonism by using 22S-alkyl vitamin D analogues. Here we report the synthesis and biological evaluation of 22R-alkyl analogues and the X-ray crystallographic analysis of vitamin D receptor ligand-binding domain (VDR-LBD) complexed with a 22R-analogue. VDR-LBD complexed with the partial agonist 8a showed that 8a binds to VDR-LBD with two conformations, one of which is the antagonist/VDR-LBD complex structure and the other is the agonist/VDR-LBD complex structure. The results indicate that the partial agonist activity of 8a depends on the sum of antagonistic and agonistic activities caused by the antagonist and agonist binding conformers, respectively. The structural basis observed here must be applicable to the partial agonism of other ligand-dependent nuclear receptors. This is the first report describing the trapping of a conformational subset of the ligand and the nuclear receptor in a single crystal.
 
A Mixed Population of Antagonist and Agonist Binding Conformers in a Single Crystal Explains Partial Agonism against Vitamin D Receptor: Active Vitamin D Analogues with 22R-Alkyl Group.,Anami Y, Itoh T, Egawa D, Yoshimoto N, Yamamoto K J Med Chem. 2014 May 22;57(10):4351-67. doi: 10.1021/jm500392t. Epub 2014 Apr 29. PMID:24742174<ref>PMID:24742174</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Vitamin D receptor 3D structures|Vitamin D receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Anami, Y.]]
[[Category: Homo sapiens]]
[[Category: Itoh, T.]]
[[Category: Large Structures]]
[[Category: Yamamoto, K.]]
[[Category: Rattus norvegicus]]
[[Category: Co-factor]]
[[Category: Anami Y]]
[[Category: Nuclear]]
[[Category: Itoh T]]
[[Category: Rxr]]
[[Category: Yamamoto K]]
[[Category: Transcription]]
[[Category: Vdre]]
[[Category: Vitamin d3]]

Latest revision as of 11:47, 20 March 2024

A mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl groupA mixed population of antagonist and agonist binding conformers in a single crystal explains partial agonism against vitamin D receptor: Active vitamin D analogues with 22R-alkyl group

Structural highlights

3wt6 is a 2 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

VDR_RAT 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. Recruited to promoters via its interaction with the WINAC complex subunit BAZ1B/WSTF, which mediates the interaction with acetylated histones, an essential step for VDR-promoter association. Plays a central role in calcium homeostasis.[1]

See Also

References

  1. ↑ Vanhooke JL, Tadi BP, Benning MM, Plum LA, DeLuca HF. New analogs of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 with conformationally restricted side chains: evaluation of biological activity and structural determination of VDR-bound conformations. Arch Biochem Biophys. 2007 Apr 15;460(2):161-5. Epub 2006 Dec 12. PMID:17227670 doi:10.1016/j.abb.2006.11.029

3wt6, resolution 2.00Å

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