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| | ==Structural basis for the accommodation of bis- and tris-aromatic derivatives in Vitamin D Nuclear Receptor== | | ==Structural basis for the accommodation of bis- and tris-aromatic derivatives in Vitamin D Nuclear Receptor== |
| - | <StructureSection load='4g21' size='340' side='right' caption='[[4g21]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4g21' size='340' side='right'caption='[[4g21]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4g21]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Danio_rerio Danio rerio]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4G21 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4G21 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4g21]] 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=4G21 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G21 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0VP:3-(5-{[3,4-BIS(HYDROXYMETHYL)BENZYL]OXY}-2-ETHYL-2-PROPYLBIPHENYL-4-YL)PENTAN-3-OL'>0VP</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]] 2.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4g1d|4g1d]], [[4g1y|4g1y]], [[4g1z|4g1z]], [[4g20|4g20]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0VP:3-(5-{[3,4-BIS(HYDROXYMETHYL)BENZYL]OXY}-2-ETHYL-2-PROPYLBIPHENYL-4-YL)PENTAN-3-OL'>0VP</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=4g21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g21 OCA], [https://pdbe.org/4g21 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g21 RCSB], [https://www.ebi.ac.uk/pdbsum/4g21 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g21 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] </span></td></tr>
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| - | <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=4g21 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g21 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4g21 RCSB], [http://www.ebi.ac.uk/pdbsum/4g21 PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/NCOA1_HUMAN NCOA1_HUMAN]] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. | |
| | == 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/NCOA1_HUMAN NCOA1_HUMAN]] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.<ref>PMID:9427757</ref> <ref>PMID:7481822</ref> <ref>PMID:9223431</ref> <ref>PMID:9296499</ref> <ref>PMID:9223281</ref> <ref>PMID:10449719</ref> <ref>PMID:12954634</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;">
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| - | == Publication Abstract from PubMed ==
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| - | Actual use of the active form of vitamin D (calcitriol or 1alpha,25-dihydroxyvitamin D(3)) to treat hyperproliferative disorders is hampered by calcemic effects, hence the continuous development of chemically modified analogues with dissociated profiles. Structurally distinct nonsecosteroidal analogues have been developed to mimic calcitriol activity profiles with low calcium serum levels. Here, we report the crystallographic study of vitamin D nuclear receptor (VDR) ligand binding domain in complexes with six nonsecosteroidal analogues harboring two or three phenyl rings. These compounds induce a stimulated transcription in the nanomolar range, similar to calcitriol. Examination of the protein-ligand interactions reveals the mode of binding of these nonsecosteroidal compounds and highlights the role of the various chemical modifications of the ligands to VDR binding and activity, notably (de)solvation effects. The structures with the tris-aromatic ligands exhibit a rearrangement of a novel region of the VDR ligand binding pocket, helix H6.
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| - | Structural Basis for the Accommodation of Bis- and Tris-Aromatic Derivatives in Vitamin D Nuclear Receptor.,Ciesielski F, Sato Y, Chebaro Y, Moras D, Dejaegere A, Rochel N J Med Chem. 2012 Sep 19. PMID:22957834<ref>PMID:22957834</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Danio rerio]] | | [[Category: Danio rerio]] |
| - | [[Category: Histone acetyltransferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ciesielski, F]] | + | [[Category: Large Structures]] |
| - | [[Category: Moras, D]] | + | [[Category: Ciesielski F]] |
| - | [[Category: Rochel, N]] | + | [[Category: Moras D]] |
| - | [[Category: Sato, Y]] | + | [[Category: Rochel N]] |
| - | [[Category: Alpha helical sandwich]]
| + | [[Category: Sato Y]] |
| - | [[Category: Dna]]
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| - | [[Category: Ligand]]
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| - | [[Category: Nuclear receptor]]
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| - | [[Category: Nucleus]]
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| - | [[Category: Phosphorylation]]
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| - | [[Category: Transcription regulation]]
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| - | [[Category: Transcription-transcription inhibitor complex]]
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| - | [[Category: Vdr]]
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