4fhi

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Development of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition

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 <StructureSection load='4fhi' size='340' side='right'caption='[[4fhi]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4fhi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Brachidanio_rerio Brachidanio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FHI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4fhi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Danio_rerio Danio rerio] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FHI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0S4:N-HYDROXY-2-{4-[3-(4-{[(2R)-2-HYDROXY-3,3-DIMETHYLBUTYL]OXY}-3-METHYLPHENYL)PENTAN-3-YL]-2-METHYLPHENOXY}ACETAMIDE'>0S4</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]] 2.4&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[4fhh|4fhh]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0S4:N-HYDROXY-2-{4-[3-(4-{[(2R)-2-HYDROXY-3,3-DIMETHYLBUTYL]OXY}-3-METHYLPHENYL)PENTAN-3-YL]-2-METHYLPHENOXY}ACETAMIDE'>0S4</scene></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=4fhi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fhi OCA], [https://pdbe.org/4fhi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fhi RCSB], [https://www.ebi.ac.uk/pdbsum/4fhi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fhi ProSAT]</span></td></tr>
 </table>
-<div style="background-color:#fffaf0;">
+== Function ==
-== Publication Abstract from PubMed ==
+[https://www.uniprot.org/uniprot/VDRA_DANRE VDRA_DANRE] 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. Plays a central role in calcium homeostasis.<ref>PMID:17218092</ref>
-,25-Dihydroxyvitamin D(3) (1,25D), the hormonal form of vitamin D, and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance. However, 1,25D analogs are amenable to bifunctionalization. Preclinical studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors (HDACi). Secosteroidal hybrid molecules combining vitamin D receptor (VDR) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize. Here, we have developed easily assembled, fully integrated, non-secosteroidal VDR agonist/HDACi hybrids. The most promising are full VDR agonists with approximately 10-fold lower potency than 1,25D. Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi. Remarkably, modeling and X-ray crystallography reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts.
-Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition.,Fischer J, Wang TT, Kaldre D, Rochel N, Moras D, White JH, Gleason JL Chem Biol. 2012 Aug 24;19(8):963-71. PMID:22921063<ref>PMID:22921063</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 4fhi" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Brachidanio rerio]]
+[[Category: Danio rerio]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Fischer, J]]
+[[Category: Fischer J]]
-[[Category: Gleason, J L]]
+[[Category: Gleason JL]]
-[[Category: Kaldre, D]]
+[[Category: Kaldre D]]
-[[Category: Moras, D]]
+[[Category: Moras D]]
-[[Category: Rochel, N]]
+[[Category: Rochel N]]
-[[Category: Wang, T T]]
+[[Category: Wang TT]]
-[[Category: White, J H]]
+[[Category: White JH]]
-[[Category: Alpha helical sandwich]]
-[[Category: Dna coregulator]]
-[[Category: Ligand binding domain alpha helical sandwich]]
-[[Category: Nucleus]]
-[[Category: Phosphorylation]]
-[[Category: Transcription factor]]
-[[Category: Transcription-protein binding-inhibitor complex]]

4fhi

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Development of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition

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