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{{STRUCTURE_3w0h|  PDB=3w0h  |  SCENE=  }}
==Crystal Structure of Rat VDR Ligand Binding Domain in Complex with Novel Nonsecosteroidal Ligands==
===Crystal Structure of Rat VDR Ligand Binding Domain in Complex with Novel Nonsecosteroidal Ligands===
<StructureSection load='3w0h' size='340' side='right' caption='[[3w0h]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
{{ABSTRACT_PUBMED_23462137}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3w0h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bionectria_wenpingii Bionectria wenpingii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W0H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W0H FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=W12:(2S)-3-{4-[4-(4-{[(2R)-2-HYDROXY-3,3-DIMETHYLBUTYL]OXY}PHENYL)HEPTAN-4-YL]PHENOXY}PROPANE-1,2-DIOL'>W12</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3w0g|3w0g]], [[3w0i|3w0i]], [[3w0j|3w0j]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Vdr, Nr1i1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=466134 Bionectria wenpingii])</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=3w0h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w0h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w0h RCSB], [http://www.ebi.ac.uk/pdbsum/3w0h PDBsum]</span></td></tr>
</table>
== Function ==
[[http://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>  [[http://www.uniprot.org/uniprot/MED1_HUMAN MED1_HUMAN]] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.<ref>PMID:9653119</ref> <ref>PMID:10406464</ref> <ref>PMID:12218053</ref> <ref>PMID:12037571</ref> <ref>PMID:11867769</ref> <ref>PMID:12556447</ref> <ref>PMID:14636573</ref> <ref>PMID:15471764</ref> <ref>PMID:15340084</ref> <ref>PMID:15989967</ref> <ref>PMID:16574658</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.


==Function==
Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands.,Asano L, Ito I, Kuwabara N, Waku T, Yanagisawa J, Miyachi H, Shimizu T FEBS Lett. 2013 Apr 2;587(7):957-63. doi: 10.1016/j.febslet.2013.02.028. Epub, 2013 Feb 24. PMID:23462137<ref>PMID:23462137</ref>
[[http://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>  [[http://www.uniprot.org/uniprot/MED1_HUMAN MED1_HUMAN]] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.<ref>PMID:9653119</ref> <ref>PMID:10406464</ref> <ref>PMID:12218053</ref> <ref>PMID:12037571</ref> <ref>PMID:11867769</ref> <ref>PMID:12556447</ref> <ref>PMID:14636573</ref> <ref>PMID:15471764</ref> <ref>PMID:15340084</ref> <ref>PMID:15989967</ref> <ref>PMID:16574658</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3w0h]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bionectria_wenpingii Bionectria wenpingii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3W0H OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:023462137</ref><references group="xtra"/><references/>
*[[Vitamin D receptor|Vitamin D receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bionectria wenpingii]]
[[Category: Bionectria wenpingii]]
[[Category: Asano, L.]]
[[Category: Asano, L]]
[[Category: Ito, I.]]
[[Category: Ito, I]]
[[Category: Kuwabara, N.]]
[[Category: Kuwabara, N]]
[[Category: Miyachi, H.]]
[[Category: Miyachi, H]]
[[Category: Shimizu, T.]]
[[Category: Shimizu, T]]
[[Category: Waku, T.]]
[[Category: Waku, T]]
[[Category: Yanagisawa, J.]]
[[Category: Yanagisawa, J]]
[[Category: Gene regulation]]
[[Category: Gene regulation]]
[[Category: Transcription]]
[[Category: Transcription]]

Revision as of 02:51, 25 December 2014

Crystal Structure of Rat VDR Ligand Binding Domain in Complex with Novel Nonsecosteroidal LigandsCrystal Structure of Rat VDR Ligand Binding Domain in Complex with Novel Nonsecosteroidal Ligands

Structural highlights

3w0h is a 2 chain structure with sequence from Bionectria wenpingii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:Vdr, Nr1i1 (Bionectria wenpingii)
Resources:FirstGlance, OCA, RCSB, PDBsum

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] [MED1_HUMAN] Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Publication Abstract from PubMed

Non-secosteroidal ligands for vitamin D receptor (VDR) have been developed for the agonist with non-calcemic profiles. Here, we provide the structural mechanism of VDR agonism by novel non-secosteroidal ligands. All ligands had the similar efficacy, while two had the higher potency. Crystallographic analyses revealed that all ligands interacted with helix H10 and the loop between helices H6 and H7 in a similar manner, but also that the two ligands with higher potency had different interaction modes. This study suggests that distinct ligand potency depend upon differences in the formation and rearrangement of hydrogen-bond networks induced by each ligand.

Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands.,Asano L, Ito I, Kuwabara N, Waku T, Yanagisawa J, Miyachi H, Shimizu T FEBS Lett. 2013 Apr 2;587(7):957-63. doi: 10.1016/j.febslet.2013.02.028. Epub, 2013 Feb 24. PMID:23462137[13]

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

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
  2. ↑ Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG. The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7939-44. PMID:9653119
  3. ↑ Zhang J, Fondell JD. Identification of mouse TRAP100: a transcriptional coregulatory factor for thyroid hormone and vitamin D receptors. Mol Endocrinol. 1999 Jul;13(7):1130-40. PMID:10406464
  4. ↑ Wang Q, Sharma D, Ren Y, Fondell JD. A coregulatory role for the TRAP-mediator complex in androgen receptor-mediated gene expression. J Biol Chem. 2002 Nov 8;277(45):42852-8. Epub 2002 Sep 5. PMID:12218053 doi:10.1074/jbc.M206061200
  5. ↑ Ge K, Guermah M, Yuan CX, Ito M, Wallberg AE, Spiegelman BM, Roeder RG. Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis. Nature. 2002 May 30;417(6888):563-7. PMID:12037571 doi:10.1038/417563a
  6. ↑ Kang YK, Guermah M, Yuan CX, Roeder RG. The TRAP/Mediator coactivator complex interacts directly with estrogen receptors alpha and beta through the TRAP220 subunit and directly enhances estrogen receptor function in vitro. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2642-7. Epub 2002 Feb 26. PMID:11867769 doi:10.1073/pnas.261715899
  7. ↑ Coulthard VH, Matsuda S, Heery DM. An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220. J Biol Chem. 2003 Mar 28;278(13):10942-51. Epub 2003 Jan 29. PMID:12556447 doi:10.1074/jbc.M212950200
  8. ↑ Wallberg AE, Yamamura S, Malik S, Spiegelman BM, Roeder RG. Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol Cell. 2003 Nov;12(5):1137-49. PMID:14636573
  9. ↑ Wu Q, Burghardt R, Safe S. Vitamin D-interacting protein 205 (DRIP205) coactivation of estrogen receptor alpha (ERalpha) involves multiple domains of both proteins. J Biol Chem. 2004 Dec 17;279(51):53602-12. Epub 2004 Oct 5. PMID:15471764 doi:10.1074/jbc.M409778200
  10. ↑ Malik S, Guermah M, Yuan CX, Wu W, Yamamura S, Roeder RG. Structural and functional organization of TRAP220, the TRAP/mediator subunit that is targeted by nuclear receptors. Mol Cell Biol. 2004 Sep;24(18):8244-54. PMID:15340084 doi:10.1128/MCB.24.18.8244-8254.2004
  11. ↑ Zhang X, Krutchinsky A, Fukuda A, Chen W, Yamamura S, Chait BT, Roeder RG. MED1/TRAP220 exists predominantly in a TRAP/ Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. Mol Cell. 2005 Jul 1;19(1):89-100. PMID:15989967 doi:10.1016/j.molcel.2005.05.015
  12. ↑ Udayakumar TS, Belakavadi M, Choi KH, Pandey PK, Fondell JD. Regulation of Aurora-A kinase gene expression via GABP recruitment of TRAP220/MED1. J Biol Chem. 2006 May 26;281(21):14691-9. Epub 2006 Mar 30. PMID:16574658 doi:M600163200
  13. ↑ Asano L, Ito I, Kuwabara N, Waku T, Yanagisawa J, Miyachi H, Shimizu T. Structural basis for vitamin D receptor agonism by novel non-secosteroidal ligands. FEBS Lett. 2013 Apr 2;587(7):957-63. doi: 10.1016/j.febslet.2013.02.028. Epub, 2013 Feb 24. PMID:23462137 doi:http://dx.doi.org/10.1016/j.febslet.2013.02.028

3w0h, resolution 1.80Å

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