5ick - Revision history

OCA at 09:16, 20 March 2024

2024-03-20T09:16:40Z

←Older revision		Revision as of 09:16, 20 March 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>		[https://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce the conformational change of FXR that modulates its binding to coregulators, resulting in distinctive functional profiles of FXR. However, the mechanisms for selectively recruiting coregulators by FXR remain elusive, partly due to the lack of FXR selective modulators. We report here the identification of two natural terpenoids, tschimgine and feroline, as a novel class of FXR modulators. Remarkably, crystal structures uncover a secondary binding-induced pocket important for ligand binding. Further, tschimgine or feroline induces dynamic conformational changes in the activation function 2 (AF-2) surface, leading to differential coregulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique for specific coregulators. Our findings thus provide a novel structure template and optimization basis for FXR selective modulators with clinical values.
-
-	A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Coregulator Assembly.,Zheng W, Lu Y, Lin S, Wang R, Qiu L, Zhu Y, Yao B, Guo F, Jin S, Jin L, Li Y Chembiochem. 2017 Feb 10. doi: 10.1002/cbic.201700059. PMID:28186695<ref>PMID:28186695</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5ick" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 13:45, 30 August 2023

2023-08-30T13:45:43Z

←Older revision		Revision as of 13:45, 30 August 2023
Line 3:		Line 3:
	<StructureSection load='5ick' size='340' side='right'caption='[[5ick]], [[Resolution\|resolution]] 2.47Å' scene=''>		<StructureSection load='5ick' size='340' side='right'caption='[[5ick]], [[Resolution\|resolution]] 2.47Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ick]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5ICK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ick]] 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=5ICK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ICK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FEZ:(1S,2S,3Z,5S,8Z)-5-HYDROXY-5,9-DIMETHYL-2-(PROPAN-2-YL)CYCLODECA-3,8-DIEN-1-YL+4-HYDROXYBENZOATE'>FEZ</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]] 2.47Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NR1H4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NCOA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FEZ:(1S,2S,3Z,5S,8Z)-5-HYDROXY-5,9-DIMETHYL-2-(PROPAN-2-YL)CYCLODECA-3,8-DIEN-1-YL+4-HYDROXYBENZOATE'>FEZ</scene></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=5ick FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ick OCA], [~~http~~://pdbe.org/5ick PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5ick RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5ick PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5ick 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=5ick FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ick OCA], [https://pdbe.org/5ick PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ick RCSB], [https://www.ebi.ac.uk/pdbsum/5ick PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ick ProSAT]</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/NR1H4_HUMAN NR1H4_HUMAN]] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</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/NR1H4_HUMAN NR1H4_HUMAN] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Li, Y]]	+	[[Category: Li Y]]
-	[[Category: Lu, Y]]	+	[[Category: Lu Y]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Transcription~~]]	+

OCA at 07:13, 3 June 2020

2020-06-03T07:13:14Z

←Older revision		Revision as of 07:13, 3 June 2020
Line 1:		Line 1:

	==A unique binding model of FXR LBD with feroline==		==A unique binding model of FXR LBD with feroline==
-	<StructureSection load='5ick' size='340' side='right' caption='[[5ick]], [[Resolution\|resolution]] 2.47Å' scene=''>	+	<StructureSection load='5ick' size='340' side='right'caption='[[5ick]], [[Resolution\|resolution]] 2.47Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ick]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICK OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5ICK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ick]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ICK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FEZ:(1S,2S,3Z,5S,8Z)-5-HYDROXY-5,9-DIMETHYL-2-(PROPAN-2-YL)CYCLODECA-3,8-DIEN-1-YL+4-HYDROXYBENZOATE'>FEZ</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FEZ:(1S,2S,3Z,5S,8Z)-5-HYDROXY-5,9-DIMETHYL-2-(PROPAN-2-YL)CYCLODECA-3,8-DIEN-1-YL+4-HYDROXYBENZOATE'>FEZ</scene></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=5ick FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ick OCA], [http://pdbe.org/5ick PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ick RCSB], [http://www.ebi.ac.uk/pdbsum/5ick PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ick ProSAT]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NR1H4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NCOA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5ick FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ick OCA], [http://pdbe.org/5ick PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ick RCSB], [http://www.ebi.ac.uk/pdbsum/5ick PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ick ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 5ick" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5ick" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Bile acid receptor 3D structures\|Bile acid receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Li, Y]]		[[Category: Li, Y]]
	[[Category: Lu, Y]]		[[Category: Lu, Y]]
	[[Category: Complex]]		[[Category: Complex]]
	[[Category: Transcription]]		[[Category: Transcription]]

OCA at 16:46, 9 March 2017

2017-03-09T16:46:49Z

←Older revision		Revision as of 16:46, 9 March 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5ick is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==A unique binding model of FXR LBD with feroline==
		+	<StructureSection load='5ick' size='340' side='right' caption='[[5ick]], [[Resolution\|resolution]] 2.47Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ick]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ICK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ICK FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FEZ:(1S,2S,3Z,5S,8Z)-5-HYDROXY-5,9-DIMETHYL-2-(PROPAN-2-YL)CYCLODECA-3,8-DIEN-1-YL+4-HYDROXYBENZOATE'>FEZ</scene></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=5ick FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ick OCA], [http://pdbe.org/5ick PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ick RCSB], [http://www.ebi.ac.uk/pdbsum/5ick PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ick ProSAT]</span></td></tr>
		+	</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 ==
		+	[[http://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN]] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce the conformational change of FXR that modulates its binding to coregulators, resulting in distinctive functional profiles of FXR. However, the mechanisms for selectively recruiting coregulators by FXR remain elusive, partly due to the lack of FXR selective modulators. We report here the identification of two natural terpenoids, tschimgine and feroline, as a novel class of FXR modulators. Remarkably, crystal structures uncover a secondary binding-induced pocket important for ligand binding. Further, tschimgine or feroline induces dynamic conformational changes in the activation function 2 (AF-2) surface, leading to differential coregulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique for specific coregulators. Our findings thus provide a novel structure template and optimization basis for FXR selective modulators with clinical values.

-	~~Authors:~~ Lu, Y., Li, Y.	+	A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Coregulator Assembly.,Zheng W, Lu Y, Lin S, Wang R, Qiu L, Zhu Y, Yao B, Guo F, Jin S, Jin L, Li Y Chembiochem. 2017 Feb 10. doi: 10.1002/cbic.201700059. PMID:28186695<ref>PMID:28186695</ref>

-	~~Description: A unique binding model~~ of ~~FXR LBD with feroline~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
		+	<div class="pdbe-citations 5ick" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Li, Y]]		[[Category: Li, Y]]
	[[Category: Lu, Y]]		[[Category: Lu, Y]]
		+	[[Category: Complex]]
		+	[[Category: Transcription]]

OCA at 14:21, 9 December 2016

2016-12-09T14:21:29Z

←Older revision		Revision as of 14:21, 9 December 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ick is ON HOLD until ~~sometime in the future~~	+	The entry 5ick is ON HOLD until Paper Publication

	Authors: Lu, Y., Li, Y.		Authors: Lu, Y., Li, Y.

OCA at 11:53, 20 June 2016

2016-06-20T11:53:39Z

←Older revision		Revision as of 11:53, 20 June 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ick is ON HOLD	+	The entry 5ick is ON HOLD until sometime in the future

	Authors: Lu, Y., Li, Y.		Authors: Lu, Y., Li, Y.

OCA: Protected "5ick" [edit=sysop:move=sysop]

2016-03-02T13:44:03Z

Protected "5ick" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:44, 2 March 2016

OCA: New page: '''Unreleased structure''' The entry 5ick is ON HOLD Authors: Lu, Y., Li, Y. Description: A unique binding model of FXR LBD with feroline Category: Unreleased Structures [[Category...

2016-03-02T13:44:01Z

New page: '''Unreleased structure''' The entry 5ick is ON HOLD Authors: Lu, Y., Li, Y. Description: A unique binding model of FXR LBD with feroline Category: Unreleased Structures [[Category...

New page

'''Unreleased structure'''

The entry 5ick is ON HOLD

Authors: Lu, Y., Li, Y.

Description: A unique binding model of FXR LBD with feroline
[[Category: Unreleased Structures]]
[[Category: Li, Y]]
[[Category: Lu, Y]]