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| | ==2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation and crystal structure== | | ==2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs: Synthesis, biological evaluation and crystal structure== |
| - | <StructureSection load='2zl9' size='340' side='right' caption='[[2zl9]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='2zl9' size='340' side='right'caption='[[2zl9]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2zl9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZL9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZL9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2zl9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ZL9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZL9 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VDA:(1R,2R,3R,5Z)-17-{(1S)-1-[(2-ETHYL-2-HYDROXYBUTYL)SULFANYL]ETHYL}-2-(2-HYDROXYETHOXY)-9,10-SECOESTRA-5,7,16-TRIENE-1,3-DIOL'>VDA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2zla|2zla]], [[2zlc|2zlc]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VDA:(1R,2R,3R,5Z)-17-{(1S)-1-[(2-ETHYL-2-HYDROXYBUTYL)SULFANYL]ETHYL}-2-(2-HYDROXYETHOXY)-9,10-SECOESTRA-5,7,16-TRIENE-1,3-DIOL'>VDA</scene></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=10116 Buffalo rat])</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=2zl9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zl9 OCA], [https://pdbe.org/2zl9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zl9 RCSB], [https://www.ebi.ac.uk/pdbsum/2zl9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zl9 ProSAT]</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=2zl9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zl9 OCA], [http://pdbe.org/2zl9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2zl9 RCSB], [http://www.ebi.ac.uk/pdbsum/2zl9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2zl9 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == 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> | + | [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> |
| | == 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/zl/2zl9_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zl/2zl9_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> |
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| | ==See Also== | | ==See Also== |
| | *[[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/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Ikura, T]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Ito, N]] | + | [[Category: Ikura T]] |
| - | [[Category: Masuno, H]] | + | [[Category: Ito N]] |
| - | [[Category: Miyamoto, Y]] | + | [[Category: Masuno H]] |
| - | [[Category: Nakabayashi, M]] | + | [[Category: Miyamoto Y]] |
| - | [[Category: Shimizu, M]] | + | [[Category: Nakabayashi M]] |
| - | [[Category: Dna-binding]]
| + | [[Category: Shimizu M]] |
| - | [[Category: Hormone]]
| + | |
| - | [[Category: Metal-binding]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protein-ligand complex]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Zinc-finger]]
| + | |
| Structural highlights
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]
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
Recently, we have found that 16-ene-22-thia-26,27-dimethyl-19-norvitamin D(3) analogs 1a (n=2, 3) are 20 times more active than the natural hormone 1alpha,25-dihydroxyvitamin D(3) in terms of transcriptional activity. To further investigate the effects of the A-ring modification of 1a, b on the biological activity profile, novel 22-thia-19-norvitamin D analogs 2-11 bearing a hydroxyethoxy-, hydroxyethylidene- or methyl group at C-2 in combination with 20S- and 20R-isomers were prepared and tested for their in vitro biological activities. All of the synthesized analogs showed 0.5-140% of the activity of the natural hormone in binding to the vitamin D receptor (VDR). When compared with the transcriptional activity of C-2 or C-20 isomeric pairs of the 22-thia analogs, the 20S-isomers 2-11a were more potent than the 20R-isomers 2, 3, 8-11b, and the 2beta-hydroxyethoxy, 2E-hydroxyethylidene, and 2alpha-methyl-2beta-hydroxy-22-thia isomers showed higher potency than their corresponding counterparts. In particular, 3a exhibited an extremely higher level of potency (210-fold) than the natural hormone. To elucidate the action mode of superagonist 3a at the molecular level, we determined the crystal structures of the rat VDR-ligand-binding domain complexed with 3a or 3b in the presence of peptide containing a nuclear box motif (LxxLL) at 1.9-2.0A resolution. The crystal structures demonstrated that the 1alpha-OH, 3beta-OH, and 25-OH groups of the natural hormone and 3a were anchored by the same amino acid residues in the ligand-binding pocket, and the terminal OH moiety of the substituent at C-2 formed hydrogen bonds with Arg270 and a water molecule to create a tight water molecule network. Moreover, the methyl groups at C-26a and C-27a make additional contact with hydrophobic residues such as Leu223, Ala227, Val230, and Ala299. These hydrophilic and hydrophobic interactions in 3a may underlie the induction of superagonistic activity.
2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvita min D3 analogs: Synthesis, biological evaluation, and crystal structure.,Shimizu M, Miyamoto Y, Takaku H, Matsuo M, Nakabayashi M, Masuno H, Udagawa N, DeLuca HF, Ikura T, Ito N Bioorg Med Chem. 2008 Jul 15;16(14):6949-64. Epub 2008 May 27. PMID:18539034[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Shimizu M, Miyamoto Y, Takaku H, Matsuo M, Nakabayashi M, Masuno H, Udagawa N, DeLuca HF, Ikura T, Ito N. 2-Substituted-16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvita min D3 analogs: Synthesis, biological evaluation, and crystal structure. Bioorg Med Chem. 2008 Jul 15;16(14):6949-64. Epub 2008 May 27. PMID:18539034 doi:10.1016/j.bmc.2008.05.043
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