5awj

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Crystal structure of VDR-LBD/partial agonist complex: 22S-hexyl analogue

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 ==Crystal structure of VDR-LBD/partial agonist complex: 22S-hexyl analogue==
-<StructureSection load='5awj' size='340' side='right' caption='[[5awj]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='5awj' size='340' side='right'caption='[[5awj]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5awj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AWJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AWJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5awj]] 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=5AWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AWJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=YSL:(1R,3R)-5-[(2E)-2-[(1R,3AS,7AR)-1-[(2R,3S)-3-(2-HYDROXYETHYL)NONAN-2-YL]-7A-METHYL-2,3,3A,5,6,7-HEXAHYDRO-1H-INDEN-4-YLIDENE]ETHYLIDENE]-2-METHYLIDENE-CYCLOHEXANE-1,3-DIOL'>YSL</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]] 2.2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5awk|5awk]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=YSL:(1R,3R)-5-[(2E)-2-[(1R,3AS,7AR)-1-[(2R,3S)-3-(2-HYDROXYETHYL)NONAN-2-YL]-7A-METHYL-2,3,3A,5,6,7-HEXAHYDRO-1H-INDEN-4-YLIDENE]ETHYLIDENE]-2-METHYLIDENE-CYCLOHEXANE-1,3-DIOL'>YSL</scene></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=5awj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awj OCA], [http://pdbe.org/5awj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5awj RCSB], [http://www.ebi.ac.uk/pdbsum/5awj 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=5awj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5awj OCA], [https://pdbe.org/5awj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5awj RCSB], [https://www.ebi.ac.uk/pdbsum/5awj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5awj ProSAT]</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>
+[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>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-alpha,25-Dihydroxyvitamin D3 exerts its actions by binding to vitamin D receptor (VDR). We are continuing the study related to the alteration of pocket structure of VDR by 22-alkyl substituent of ligands and the relationships between the alteration and agonistic/antagonistic activity. Previously we reported that compounds 2 (22-H), 3 (22S-Et), and 4 (22S-Bu) are VDR agonist, partial agonist and antagonist, respectively. Here, we describe the synthesis and biological evaluation of 22S-hexyl analog 5 (22S-Hex), which was designed to be a stronger VDR antagonist than 4. Unexpectedly, 5 showed partial agonistic but not antagonistic activity when bound to VDR, indicating that it is not necessarily true that the bulkier the side chain is, the stronger the antagonistic activity will be. X-ray crystallographic analysis of the VDR-ligand-binding domain (VDR-LBD) accommodating compound 5 indicated that the partial agonist activity of 5 is dependent on the mixed population of the agonistic and antagonistic conformations. Binding of compound 5 may not bring the complex into the only antagonistic conformation due to the large conformational change of the VDR-LBD. From this study it was found that fine tuning of agonistic/antagonistic activity for VDR is possible by 22-alkyl chain length of ligands.
-Fine tuning of agonistic/antagonistic activity for vitamin D receptor by 22-alkyl chain length of ligands: 22S-Hexyl compound unexpectedly restored agonistic activity.,Anami Y, Sakamaki Y, Itoh T, Inaba Y, Nakabayashi M, Ikura T, Ito N, Yamamoto K Bioorg Med Chem. 2015 Nov 15;23(22):7274-81. doi: 10.1016/j.bmc.2015.10.026. Epub, 2015 Oct 26. PMID:26515040<ref>PMID:26515040</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]]
-<div class="pdbe-citations 5awj" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Anami, Y]]
+[[Category: Homo sapiens]]
-[[Category: Ikura, T]]
+[[Category: Large Structures]]
-[[Category: Inaba, Y]]
+[[Category: Rattus norvegicus]]
-[[Category: Ito, N]]
+[[Category: Anami Y]]
-[[Category: Itoh, T]]
+[[Category: Ikura T]]
-[[Category: Nakabayashi, M]]
+[[Category: Inaba Y]]
-[[Category: Yamamoto, K]]
+[[Category: Ito N]]
-[[Category: Co-factor]]
+[[Category: Itoh T]]
-[[Category: Rxr]]
+[[Category: Nakabayashi M]]
-[[Category: Transcription]]
+[[Category: Yamamoto K]]
-[[Category: Vdre]]
-[[Category: Vitamin d3]]

5awj

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Crystal structure of VDR-LBD/partial agonist complex: 22S-hexyl analogue

Structural highlights

Function

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