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5ow7

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Revision as of 07:32, 2 September 2020

VDR complex

Structural highlights

5ow7 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	2hc4, 5mx7
Activity:	Histone acetyltransferase, with EC number 2.3.1.48
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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

[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.^[1] [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.^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

20S-hydroxyvitamin D3 [20S(OH)D3] is anti-inflammatory and not hypercalcemic, suggesting its potential as a lead compound. In this study, side chain modified 20S(OH)D3 analogs (4, 13, 23 and 33) together with their 1alpha-OH derivatives were synthesized and their metabolism and biological activities tested. 4, 13 and 23 are good substrates for CYP27B1, enabling enzymatic synthesis of their 1alpha-OH derivatives 5, 14 and 24. However, 33 could not be hydroxylated by CYP27B1 and acts as an inhibitor. All analogs were poorer substrates for CYP24A1 than calcitriol, indicating improved catabolic stability. While the parent analogs showed minimal VDR stimulating activity, their 1alpha-OH derivatives were potent VDR agonists. 4, 5, 14 and 24 significantly upregulated the expression of CYP24A1 at the mRNA level, consistent with their VDR activation abilities and indicating that 1alpha-hydroxylation is required to produce analogs with strong activity. These analogs have anti-inflammatory activities that are influenced by side chain composition and by 1alpha-hydroxylation. To understand their molecular interactions with the VDR, 20S(OH)D3, 4 and 33 were co-crystalized with the VDR ligand binding domain, which revealed subtle differences to the calcitriol-bound receptor. This study demonstrates the potential of the 20S(OH)D3 scaffold for the development of novel anti-inflammatory agents.

Investigation of 20S-hydroxyvitamin D3 analogs and their 1alpha-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities.,Lin Z, Marepally SR, Goh ESY, Cheng CYS, Janjetovic Z, Kim TK, Miller DD, Postlethwaite AE, Slominski AT, Tuckey RC, Peluso-Iltis C, Rochel N, Li W Sci Rep. 2018 Jan 24;8(1):1478. doi: 10.1038/s41598-018-19183-7. PMID:29367669^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003
↑ Kalkhoven E, Valentine JE, Heery DM, Parker MG. Isoforms of steroid receptor co-activator 1 differ in their ability to potentiate transcription by the oestrogen receptor. EMBO J. 1998 Jan 2;17(1):232-43. PMID:9427757 doi:10.1093/emboj/17.1.232
↑ Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995 Nov 24;270(5240):1354-7. PMID:7481822
↑ Hayashi Y, Ohmori S, Ito T, Seo H. A splicing variant of Steroid Receptor Coactivator-1 (SRC-1E): the major isoform of SRC-1 to mediate thyroid hormone action. Biochem Biophys Res Commun. 1997 Jul 9;236(1):83-7. PMID:9223431 doi:10.1006/bbrc.1997.6911
↑ Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194-8. PMID:9296499 doi:10.1038/38304
↑ Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor induction of gene transcription: a two-step model. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7879-84. PMID:9223281
↑ Liu Z, Wong J, Tsai SY, Tsai MJ, O'Malley BW. Steroid receptor coactivator-1 (SRC-1) enhances ligand-dependent and receptor-dependent cell-free transcription of chromatin. Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9485-90. PMID:10449719
↑ Litterst CM, Kliem S, Marilley D, Pfitzner E. NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the FDL motif in the alpha-helical region of the STAT5 transactivation domain. J Biol Chem. 2003 Nov 14;278(46):45340-51. Epub 2003 Sep 3. PMID:12954634 doi:http://dx.doi.org/10.1074/jbc.M303644200
↑ Lin Z, Marepally SR, Goh ESY, Cheng CYS, Janjetovic Z, Kim TK, Miller DD, Postlethwaite AE, Slominski AT, Tuckey RC, Peluso-Iltis C, Rochel N, Li W. Investigation of 20S-hydroxyvitamin D3 analogs and their 1alpha-OH derivatives as potent vitamin D receptor agonists with anti-inflammatory activities. Sci Rep. 2018 Jan 24;8(1):1478. doi: 10.1038/s41598-018-19183-7. PMID:29367669 doi:http://dx.doi.org/10.1038/s41598-018-19183-7

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5ow7"

@@ Line 1: / Line 1: @@
 ==VDR complex==
-<StructureSection load='5ow7' size='340' side='right' caption='[[5ow7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5ow7' size='340' side='right'caption='[[5ow7]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5ow7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OW7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5OW7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5ow7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OW7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5OW7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AYK:(3~{S})-3-[(1~{S},3~{a}~{S},4~{E},7~{a}~{S})-7~{a}-methyl-4-[(2~{Z})-2-[(5~{S})-2-methylidene-5-oxidanyl-cyclohexylidene]ethylidene]-2,3,3~{a},5,6,7-hexahydro-1~{H}-inden-1-yl]-3-oxidanyl-~{N}-propan-2-yl-butanamide'>AYK</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AYK:(3~{S})-3-[(1~{S},3~{a}~{S},4~{E},7~{a}~{S})-7~{a}-methyl-4-[(2~{Z})-2-[(5~{S})-2-methylidene-5-oxidanyl-cyclohexylidene]ethylidene]-2,3,3~{a},5,6,7-hexahydro-1~{H}-inden-1-yl]-3-oxidanyl-~{N}-propan-2-yl-butanamide'>AYK</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2hc4|2hc4]], [[5mx7|5mx7]]</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>
-<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=5ow7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ow7 OCA], [http://pdbe.org/5ow7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ow7 RCSB], [http://www.ebi.ac.uk/pdbsum/5ow7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ow7 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ow7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ow7 OCA], [http://pdbe.org/5ow7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ow7 RCSB], [http://www.ebi.ac.uk/pdbsum/5ow7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ow7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 22: @@
 </div>
 <div class="pdbe-citations 5ow7" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Vitamin D receptor 3D structures|Vitamin D receptor 3D structures]]
 == References ==
 <references/>
@@ Line 27: / Line 30: @@
 </StructureSection>
 [[Category: Histone acetyltransferase]]
+[[Category: Large Structures]]
 [[Category: Li, W]]
 [[Category: Rochel, N]]

5ow7

From Proteopedia

Revision as of 07:32, 2 September 2020

VDR complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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