4fhh: Difference between revisions

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==Development of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition==
==Development of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition==
<StructureSection load='4fhh' size='340' side='right' caption='[[4fhh]], [[Resolution|resolution]] 2.33&Aring;' scene=''>
<StructureSection load='4fhh' size='340' side='right'caption='[[4fhh]], [[Resolution|resolution]] 2.33&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4fhh]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FHH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FHH FirstGlance]. <br>
<table><tr><td colspan='2'>[[4fhh]] 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=4FHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FHH FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0U3:N-HYDROXY-2-{4-[3-(4-{[(2S)-2-HYDROXY-3,3-DIMETHYLBUTYL]OXY}-3-METHYLPHENYL)PENTAN-3-YL]-2-METHYLPHENOXY}ACETAMIDE'>0U3</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]] 2.33&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fhi|4fhi]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0U3:N-HYDROXY-2-{4-[3-(4-{[(2S)-2-HYDROXY-3,3-DIMETHYLBUTYL]OXY}-3-METHYLPHENYL)PENTAN-3-YL]-2-METHYLPHENOXY}ACETAMIDE'>0U3</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">vdra, nr1i1a, vdr ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7955 Danio rerio])</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=4fhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fhh OCA], [https://pdbe.org/4fhh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fhh RCSB], [https://www.ebi.ac.uk/pdbsum/4fhh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fhh 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=4fhh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fhh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fhh RCSB], [http://www.ebi.ac.uk/pdbsum/4fhh PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation.
== Function ==
== Function ==
[[http://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>  [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> 
[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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
1,25-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>
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Danio rerio]]
[[Category: Danio rerio]]
[[Category: Fischer, J]]
[[Category: Homo sapiens]]
[[Category: Gleason, J L]]
[[Category: Large Structures]]
[[Category: Kaldre, D]]
[[Category: Fischer J]]
[[Category: Moras, D]]
[[Category: Gleason JL]]
[[Category: Rochel, N]]
[[Category: Kaldre D]]
[[Category: Wang, T T]]
[[Category: Moras D]]
[[Category: White, J H]]
[[Category: Rochel N]]
[[Category: Adn coregulator]]
[[Category: Wang TT]]
[[Category: Alpha helical sandwich]]
[[Category: White JH]]
[[Category: Apha helical sandwich]]
[[Category: Ligand binding domain]]
[[Category: Nucleus]]
[[Category: Phosphorylation and hdac inhibitor]]
[[Category: Transcription factor]]
[[Category: Transcription-protein binding-inhibitor complex]]

Latest revision as of 11:16, 1 March 2024

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

4fhh, resolution 2.33Å

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