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==Crystal Structure of Vitamin D Receptor and 9-cis Retinoic Acid Receptor DNA-Binding Domains Bound to a DR3 Response Element==
==Crystal Structure of Vitamin D Receptor and 9-cis Retinoic Acid Receptor DNA-Binding Domains Bound to a DR3 Response Element==
<StructureSection load='1ynw' size='340' side='right' caption='[[1ynw]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
<StructureSection load='1ynw' size='340' side='right'caption='[[1ynw]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1ynw]] is a 4 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=1YNW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1YNW FirstGlance]. <br>
<table><tr><td colspan='2'>[[1ynw]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The November 2012 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Vitamin D Receptor''  by David Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2012_11 10.2210/rcsb_pdb/mom_2012_11]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YNW FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 3&#8491;</td></tr>
<tr><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=9606 Homo sapiens]), RXRA, NR2B1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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=1ynw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ynw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1ynw RCSB], [http://www.ebi.ac.uk/pdbsum/1ynw 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=1ynw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ynw OCA], [https://pdbe.org/1ynw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ynw RCSB], [https://www.ebi.ac.uk/pdbsum/1ynw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ynw ProSAT]</span></td></tr>
<table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN]] Defects in VDR are the cause of rickets vitamin D-dependent type 2A (VDDR2A) [MIM:[http://omim.org/entry/277440 277440]]. A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets.<ref>PMID:2849209</ref> <ref>PMID:8381803</ref> <ref>PMID:1652893</ref> <ref>PMID:2177843</ref> <ref>PMID:8106618</ref> <ref>PMID:8392085</ref> <ref>PMID:7828346</ref> <ref>PMID:8675579</ref> <ref>PMID:8961271</ref> <ref>PMID:9005998</ref>
[https://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN] Defects in VDR are the cause of rickets vitamin D-dependent type 2A (VDDR2A) [MIM:[https://omim.org/entry/277440 277440]. A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets.<ref>PMID:2849209</ref> <ref>PMID:8381803</ref> <ref>PMID:1652893</ref> <ref>PMID:2177843</ref> <ref>PMID:8106618</ref> <ref>PMID:8392085</ref> <ref>PMID:7828346</ref> <ref>PMID:8675579</ref> <ref>PMID:8961271</ref> <ref>PMID:9005998</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN]] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>  [[http://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN]] 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:16252006</ref> <ref>PMID:10678179</ref> <ref>PMID:15728261</ref> <ref>PMID:16913708</ref>
[https://www.uniprot.org/uniprot/VDR_HUMAN VDR_HUMAN] 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:16252006</ref> <ref>PMID:10678179</ref> <ref>PMID:15728261</ref> <ref>PMID:16913708</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/yn/1ynw_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/yn/1ynw_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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/chain_selection.php?pdb_ID=2ata 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=1ynw ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 1ynw" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Retinoid X receptor|Retinoid X receptor]]
*[[Retinoid X receptor 3D structures|Retinoid X receptor 3D structures]]
*[[Sandbox vdr|Sandbox vdr]]
*[[Sandbox vdr|Sandbox vdr]]
*[[Vitamin D receptor|Vitamin D receptor]]
*[[Vitamin D receptor 3D structures|Vitamin D receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Gewirth, D T.]]
[[Category: Large Structures]]
[[Category: Shaffer, P L.]]
[[Category: RCSB PDB Molecule of the Month]]
[[Category: Nuclear receptor]]
[[Category: Vitamin D Receptor]]
[[Category: Protein-dna complex]]
[[Category: Gewirth DT]]
[[Category: Rxr]]
[[Category: Shaffer PL]]
[[Category: Transcription-dna complex]]
[[Category: Vdr]]

Latest revision as of 09:59, 23 August 2023

Crystal Structure of Vitamin D Receptor and 9-cis Retinoic Acid Receptor DNA-Binding Domains Bound to a DR3 Response ElementCrystal Structure of Vitamin D Receptor and 9-cis Retinoic Acid Receptor DNA-Binding Domains Bound to a DR3 Response Element

Structural highlights

1ynw is a 4 chain structure with sequence from Homo sapiens. The November 2012 RCSB PDB Molecule of the Month feature on Vitamin D Receptor by David Goodsell is 10.2210/rcsb_pdb/mom_2012_11. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

VDR_HUMAN Defects in VDR are the cause of rickets vitamin D-dependent type 2A (VDDR2A) [MIM:277440. A disorder of vitamin D metabolism resulting in severe rickets, hypocalcemia and secondary hyperparathyroidism. Most patients have total alopecia in addition to rickets.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]

Function

VDR_HUMAN 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.[11] [12] [13] [14]

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

The Vitamin D receptor (VDR) is a ligand-responsive transcription factor that forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by three base pairs of spacer DNA. Binding of 1alpha,25-dihydroxyvitamin D(3) to the full-length VDR causes destabilization of the VDR homodimer and formation of a heterodimeric complex with the 9-cis retinoic acid receptor (RXR). VDR and RXR DNA-binding domains (DBDs) do not mimic this behavior, however: VDR DBD homodimers are formed exclusively, even in the presence of excess RXR DBD. Exploiting the asymmetry of the heterodimer and our knowledge of the homodimeric DBD interface, we have engineered VDR mutants that disfavor the homodimeric complex and allow for the formation of heterodimeric DBD complexes with RXR on DR3 elements. One of these complexes has been crystallized and its structure determined. However, the polarity of the proteins relative to the DNA is non-physiological due to crystal packing between symmetry-related VDR DBD protomers. This reveals a flattened energy landscape that appears to rely on elements outside of the core DBD for response element discrimination in the heterodimer.

Structural analysis of RXR-VDR interactions on DR3 DNA.,Shaffer PL, Gewirth DT J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):215-9. PMID:15225774[15]

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

See Also

References

  1. ↑ Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O'Malley BW. Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. Science. 1988 Dec 23;242(4886):1702-5. PMID:2849209
  2. ↑ Yagi H, Ozono K, Miyake H, Nagashima K, Kuroume T, Pike JW. A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol Metab. 1993 Feb;76(2):509-12. PMID:8381803
  3. ↑ Saijo T, Ito M, Takeda E, Huq AH, Naito E, Yokota I, Sone T, Pike JW, Kuroda Y. A unique mutation in the vitamin D receptor gene in three Japanese patients with vitamin D-dependent rickets type II: utility of single-strand conformation polymorphism analysis for heterozygous carrier detection. Am J Hum Genet. 1991 Sep;49(3):668-73. PMID:1652893
  4. ↑ Sone T, Marx SJ, Liberman UA, Pike JW. A unique point mutation in the human vitamin D receptor chromosomal gene confers hereditary resistance to 1,25-dihydroxyvitamin D3. Mol Endocrinol. 1990 Apr;4(4):623-31. PMID:2177843
  5. ↑ Malloy PJ, Weisman Y, Feldman D. Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain. J Clin Endocrinol Metab. 1994 Feb;78(2):313-6. PMID:8106618
  6. ↑ Kristjansson K, Rut AR, Hewison M, O'Riordan JL, Hughes MR. Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3. J Clin Invest. 1993 Jul;92(1):12-6. PMID:8392085 doi:http://dx.doi.org/10.1172/JCI116539
  7. ↑ Rut AR, Hewison M, Kristjansson K, Luisi B, Hughes MR, O'Riordan JL. Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures. Clin Endocrinol (Oxf). 1994 Nov;41(5):581-90. PMID:7828346
  8. ↑ Lin NU, Malloy PJ, Sakati N, al-Ashwal A, Feldman D. A novel mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor causes hereditary 1,25-dihydroxyvitamin D-resistant rickets. J Clin Endocrinol Metab. 1996 Jul;81(7):2564-9. PMID:8675579
  9. ↑ Whitfield GK, Selznick SH, Haussler CA, Hsieh JC, Galligan MA, Jurutka PW, Thompson PD, Lee SM, Zerwekh JE, Haussler MR. Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner. Mol Endocrinol. 1996 Dec;10(12):1617-31. PMID:8961271
  10. ↑ Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, Feldman D. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest. 1997 Jan 15;99(2):297-304. PMID:9005998 doi:10.1172/JCI119158
  11. ↑ Fujiki R, Kim MS, Sasaki Y, Yoshimura K, Kitagawa H, Kato S. Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J. 2005 Nov 16;24(22):3881-94. Epub 2005 Oct 27. PMID:16252006 doi:10.1038/sj.emboj.7600853
  12. ↑ Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000 Jan;5(1):173-9. PMID:10678179
  13. ↑ Eelen G, Verlinden L, Rochel N, Claessens F, De Clercq P, Vandewalle M, Tocchini-Valentini G, Moras D, Bouillon R, Verstuyf A. Superagonistic action of 14-epi-analogs of 1,25-dihydroxyvitamin D explained by vitamin D receptor-coactivator interaction. Mol Pharmacol. 2005 May;67(5):1566-73. Epub 2005 Feb 22. PMID:15728261 doi:10.1124/mol.104.008730
  14. ↑ Hourai S, Fujishima T, Kittaka A, Suhara Y, Takayama H, Rochel N, Moras D. Probing a water channel near the A-ring of receptor-bound 1 alpha,25-dihydroxyvitamin D3 with selected 2 alpha-substituted analogues. J Med Chem. 2006 Aug 24;49(17):5199-205. PMID:16913708 doi:http://dx.doi.org/10.1021/jm0604070
  15. ↑ Shaffer PL, Gewirth DT. Structural analysis of RXR-VDR interactions on DR3 DNA. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):215-9. PMID:15225774 doi:10.1016/j.jsbmb.2004.03.084

1ynw, resolution 3.00Å

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