7nke - Revision history

OCA at 07:52, 7 February 2024

OCA — Wed, 07 Feb 2024 07:52:34 GMT

←Older revision		Revision as of 07:52, 7 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7nke]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NKE FirstGlance]. <br>		<table><tr><td colspan='2'>[[7nke]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NKE FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=UGW:2,4-di~{tert}-butylphenol'>UGW</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]] 2.35Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=UGW:2,4-di~{tert}-butylphenol'>UGW</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=7nke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nke OCA], [https://pdbe.org/7nke PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nke RCSB], [https://www.ebi.ac.uk/pdbsum/7nke PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nke ProSAT]</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=7nke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nke OCA], [https://pdbe.org/7nke PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nke RCSB], [https://www.ebi.ac.uk/pdbsum/7nke PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nke ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>		[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	2,4-Di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. We asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor (PPAR) gamma-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARgamma/RXRalpha heterodimer by activating RXRalpha but not directly binding to PPARgamma. We confirmed that 2,4-DTBP directly bound to RXRalpha by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRalpha. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure-activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology.

-	2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors.,Ren XM, Chang RC, Huang Y, Amorim Amato A, Carivenc C, Grimaldi M, Kuo Y, Balaguer P, Bourguet W, Blumberg B Endocrinology. 2023 Feb 11;164(4):bqad021. doi: 10.1210/endocr/bqad021. PMID:36750942<ref>PMID:36750942</ref>	+	==See Also==
-		+	*[[Retinoid X receptor 3D structures\|Retinoid X receptor 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 7nke" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:59, 15 March 2023

OCA — Wed, 15 Mar 2023 09:59:51 GMT

←Older revision		Revision as of 09:59, 15 March 2023
Line 1:		Line 1:

-	====	+	==Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-tert-butylphenol and a coactivator fragment==
-	<StructureSection load='7nke' size='340' side='right'caption='[[7nke]]' scene=''>	+	<StructureSection load='7nke' size='340' side='right'caption='[[7nke]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7nke]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NKE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NKE FirstGlance]. <br>
-	</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=7nke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nke OCA], [https://pdbe.org/7nke PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nke RCSB], [https://www.ebi.ac.uk/pdbsum/7nke PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nke ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=UGW:2,4-di~{tert}-butylphenol'>UGW</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=7nke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nke OCA], [https://pdbe.org/7nke PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nke RCSB], [https://www.ebi.ac.uk/pdbsum/7nke PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nke ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/RXRA_HUMAN RXRA_HUMAN] Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.<ref>PMID:10195690</ref> <ref>PMID:11162439</ref> <ref>PMID:11915042</ref> <ref>PMID:20215566</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	2,4-Di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. We asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor (PPAR) gamma-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPARgamma/RXRalpha heterodimer by activating RXRalpha but not directly binding to PPARgamma. We confirmed that 2,4-DTBP directly bound to RXRalpha by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXRalpha. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXRs. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition. Structure-activity studies such as the present one could help guide the rational development of safer antioxidants that do not interact with important nuclear receptors having broad effects on human development and physiology.
		+
		+	2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors.,Ren XM, Chang RC, Huang Y, Amorim Amato A, Carivenc C, Grimaldi M, Kuo Y, Balaguer P, Bourguet W, Blumberg B Endocrinology. 2023 Feb 11;164(4):bqad021. doi: 10.1210/endocr/bqad021. PMID:36750942<ref>PMID:36750942</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7nke" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Bourguet W]]
		+	[[Category: Carivenc C]]

OCA at 06:18, 2 March 2022

OCA — Wed, 02 Mar 2022 06:18:27 GMT

←Older revision		Revision as of 06:18, 2 March 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7nke ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='7nke' size='340' side='right'caption='[[7nke]]' scene=''>
-	~~Authors~~: ~~Carivenc, C~~.~~, Bourguet, W~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure of human RXRalpha ligand binding domain in complex with 2~~,4-~~di-tert-butylphenol and a coactivator fragment~~	+	</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=7nke FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nke OCA], [https://pdbe.org/7nke PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nke RCSB], [https://www.ebi.ac.uk/pdbsum/7nke PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nke ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[Category: ~~Bourguet, W~~]]	+	__TOC__
-	[[Category: ~~Carivenc, C~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 13:32, 3 March 2021

OCA — Wed, 03 Mar 2021 13:32:25 GMT

←Older revision		Revision as of 13:32, 3 March 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7nke is ON HOLD	+	The entry 7nke is ON HOLD until Paper Publication

	Authors: Carivenc, C., Bourguet, W.		Authors: Carivenc, C., Bourguet, W.
Line 7:		Line 7:
	Description: Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-tert-butylphenol and a coactivator fragment		Description: Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-tert-butylphenol and a coactivator fragment
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Carivenc, C]]
	[[Category: Bourguet, W]]		[[Category: Bourguet, W]]
		+	[[Category: Carivenc, C]]

OCA: Protected "7nke" [edit=sysop:move=sysop]

OCA — Wed, 24 Feb 2021 05:48:29 GMT

Protected "7nke" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:48, 24 February 2021

OCA: New page: '''Unreleased structure''' The entry 7nke is ON HOLD Authors: Carivenc, C., Bourguet, W. Description: Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-t...

OCA — Wed, 24 Feb 2021 05:48:28 GMT

New page: '''Unreleased structure''' The entry 7nke is ON HOLD Authors: Carivenc, C., Bourguet, W. Description: Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-t...

New page

'''Unreleased structure'''

The entry 7nke is ON HOLD

Authors: Carivenc, C., Bourguet, W.

Description: Crystal structure of human RXRalpha ligand binding domain in complex with 2,4-di-tert-butylphenol and a coactivator fragment
[[Category: Unreleased Structures]]
[[Category: Carivenc, C]]
[[Category: Bourguet, W]]