6nwl - Revision history

OCA at 14:49, 13 March 2024

OCA — Wed, 13 Mar 2024 14:49:15 GMT

←Older revision		Revision as of 14:49, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6nwl' size='340' side='right'caption='[[6nwl]], [[Resolution\|resolution]] 1.59Å' scene=''>		<StructureSection load='6nwl' size='340' side='right'caption='[[6nwl]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nwl]] is a 2 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=6NWL OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6NWL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nwl]] is a 2 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=6NWL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NWL FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 1.595Å</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=6nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nwl OCA], [~~http~~://pdbe.org/6nwl PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nwl RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nwl PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nwl ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=6nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nwl OCA], [https://pdbe.org/6nwl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nwl RCSB], [https://www.ebi.ac.uk/pdbsum/6nwl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nwl ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PRGC1_HUMAN PRGC1_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.<ref>PMID:10713165</ref> <ref>PMID:20005308</ref> <ref>PMID:21376232</ref>	+	[https://www.uniprot.org/uniprot/PRGC1_HUMAN PRGC1_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.<ref>PMID:10713165</ref> <ref>PMID:20005308</ref> <ref>PMID:21376232</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Both synthetic and endogenous glucocorticoids are important pharmaceutic drugs known to bind to the ligand-binding domain (LBD) of glucocorticoid receptor (GR), a member of the nuclear receptor (NR) superfamily. Ligand binding induces conformational changes within GR, resulting in subsequent DNA binding and differential coregulator recruitment, ultimately activating or repressing target gene expression. One of the most crucial coregulators is peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1alpha), which acts to regulate energy metabolism by directly interacting with GR to modulate gene expression. However, the mechanisms through which PGC1alpha senses GR conformation to drive transcription are not completely known. Here, an ancestral variant of the GR (AncGR2) LBD was used as a tool to produce stable protein for biochemical and structural studies. PGC1alpha is found to interact more tightly and form a more stable complex with AncGR2 LBD than nuclear receptor coactivator 2. We report the first high-resolution X-ray crystal structures of AncGR2 LBD in complex with PGC1alpha and dexamethasone (DEX) or hydrocortisone (HCY). Structural analyses reveal how distinct steroid drugs bind to GR with different affinities by unique hydrogen bonds and hydrophobic interactions. Important charge clamps are formed between the activation function 2 and PGC1alpha to mediate their specific interactions. These interactions lead to a high level of protection from hydrogen-deuterium exchange at the coregulator interaction site and strong intramolecular allosteric communication to ligand binding site. This is the first structure detailing the GR-PGC1alpha interaction providing a foundation for future design of specific therapeutic agents targeting these critical metabolic regulators. SIGNIFICANCE STATEMENT: High-resolution structures of AncGR2 LBD bound to DEX and HCY in complex with PGC1alpha reveal the molecular mechanism of PGC1alpha binding to AncGR2 LBD as well as the distinct affinities between DEX and HCY binding. Identifying the structural mechanisms that drive drug affinity is of pharmacologic interest to the glucocorticoid receptor field as an avenue to guide future drug design targeting GR-PGC1alpha signaling, which plays a crucial role in controlling hepatic glucose output.	+

-	First High-Resolution Crystal Structures of the Glucocorticoid Receptor Ligand-Binding Domain-Peroxisome Proliferator-Activated gamma Coactivator 1-alpha Complex with Endogenous and Synthetic Glucocorticoids.,Liu X, Wang Y, Ortlund EA Mol Pharmacol. 2019 Oct;96(4):408-417. doi: 10.1124/mol.119.116806. Epub 2019 Aug, 7. PMID:31391291<ref>PMID:31391291</ref>	+	==See Also==
-		+	*[[Glucocorticoid receptor 3D structures\|Glucocorticoid receptor 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6nwl" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Liu, X]]	+	[[Category: Liu X]]
-	[[Category: Ortlund~~, E A]]~~	+	[[Category: Ortlund EA]]
-	~~[[Category: Agonist]]~~	+
-	~~[[Category: Coactivator]]~~	+
-	~~[[Category: Glucocorticoid receptor]]~~	+
-	~~[[Category: Hormone~~]]	+

OCA at 13:04, 25 December 2019

OCA — Wed, 25 Dec 2019 13:04:33 GMT

←Older revision		Revision as of 13:04, 25 December 2019
Line 3:		Line 3:
	<StructureSection load='6nwl' size='340' side='right'caption='[[6nwl]], [[Resolution\|resolution]] 1.59Å' scene=''>		<StructureSection load='6nwl' size='340' side='right'caption='[[6nwl]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nwl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NWL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NWL FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nwl]] is a 2 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=6NWL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NWL FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=6nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nwl OCA], [http://pdbe.org/6nwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nwl RCSB], [http://www.ebi.ac.uk/pdbsum/6nwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nwl 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=6nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nwl OCA], [http://pdbe.org/6nwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nwl RCSB], [http://www.ebi.ac.uk/pdbsum/6nwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nwl ProSAT]</span></td></tr>
Line 22:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Liu, X]]		[[Category: Liu, X]]

OCA at 06:55, 23 October 2019

OCA — Wed, 23 Oct 2019 06:55:05 GMT

←Older revision		Revision as of 06:55, 23 October 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6nwl is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with hydrocortisone and PGC1a coregulator fragment==
		+	<StructureSection load='6nwl' size='340' side='right'caption='[[6nwl]], [[Resolution\|resolution]] 1.59Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nwl]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NWL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NWL FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HCY:(11ALPHA,14BETA)-11,17,21-TRIHYDROXYPREGN-4-ENE-3,20-DIONE'>HCY</scene>, <scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=6nwl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nwl OCA], [http://pdbe.org/6nwl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nwl RCSB], [http://www.ebi.ac.uk/pdbsum/6nwl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nwl ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PRGC1_HUMAN PRGC1_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.<ref>PMID:10713165</ref> <ref>PMID:20005308</ref> <ref>PMID:21376232</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Both synthetic and endogenous glucocorticoids are important pharmaceutic drugs known to bind to the ligand-binding domain (LBD) of glucocorticoid receptor (GR), a member of the nuclear receptor (NR) superfamily. Ligand binding induces conformational changes within GR, resulting in subsequent DNA binding and differential coregulator recruitment, ultimately activating or repressing target gene expression. One of the most crucial coregulators is peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1alpha), which acts to regulate energy metabolism by directly interacting with GR to modulate gene expression. However, the mechanisms through which PGC1alpha senses GR conformation to drive transcription are not completely known. Here, an ancestral variant of the GR (AncGR2) LBD was used as a tool to produce stable protein for biochemical and structural studies. PGC1alpha is found to interact more tightly and form a more stable complex with AncGR2 LBD than nuclear receptor coactivator 2. We report the first high-resolution X-ray crystal structures of AncGR2 LBD in complex with PGC1alpha and dexamethasone (DEX) or hydrocortisone (HCY). Structural analyses reveal how distinct steroid drugs bind to GR with different affinities by unique hydrogen bonds and hydrophobic interactions. Important charge clamps are formed between the activation function 2 and PGC1alpha to mediate their specific interactions. These interactions lead to a high level of protection from hydrogen-deuterium exchange at the coregulator interaction site and strong intramolecular allosteric communication to ligand binding site. This is the first structure detailing the GR-PGC1alpha interaction providing a foundation for future design of specific therapeutic agents targeting these critical metabolic regulators. SIGNIFICANCE STATEMENT: High-resolution structures of AncGR2 LBD bound to DEX and HCY in complex with PGC1alpha reveal the molecular mechanism of PGC1alpha binding to AncGR2 LBD as well as the distinct affinities between DEX and HCY binding. Identifying the structural mechanisms that drive drug affinity is of pharmacologic interest to the glucocorticoid receptor field as an avenue to guide future drug design targeting GR-PGC1alpha signaling, which plays a crucial role in controlling hepatic glucose output.

-	~~Authors: Liu~~, X., ~~Ortlund~~, E.A.	+	First High-Resolution Crystal Structures of the Glucocorticoid Receptor Ligand-Binding Domain-Peroxisome Proliferator-Activated gamma Coactivator 1-alpha Complex with Endogenous and Synthetic Glucocorticoids.,Liu X, Wang Y, Ortlund EA Mol Pharmacol. 2019 Oct;96(4):408-417. doi: 10.1124/mol.119.116806. Epub 2019 Aug, 7. PMID:31391291<ref>PMID:31391291</ref>

-	~~Description: Structure~~ of the ~~Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with hydrocortisone and PGC1a coregulator fragment~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6nwl" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Liu, X]]		[[Category: Liu, X]]
-	[[Category: Ortlund, E.A]]	+	[[Category: Ortlund, E A]]
		+	[[Category: Agonist]]
		+	[[Category: Coactivator]]
		+	[[Category: Glucocorticoid receptor]]
		+	[[Category: Hormone]]

OCA at 13:44, 27 February 2019

OCA — Wed, 27 Feb 2019 13:44:12 GMT

←Older revision		Revision as of 13:44, 27 February 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6nwl is ON HOLD	+	The entry 6nwl is ON HOLD until Paper Publication

	Authors: Liu, X., Ortlund, E.A.		Authors: Liu, X., Ortlund, E.A.

OCA: Protected "6nwl" [edit=sysop:move=sysop]

OCA — Wed, 13 Feb 2019 07:53:01 GMT

Protected "6nwl" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:53, 13 February 2019

OCA: New page: '''Unreleased structure''' The entry 6nwl is ON HOLD Authors: Liu, X., Ortlund, E.A. Description: Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex ...

OCA — Wed, 13 Feb 2019 07:52:59 GMT

New page: '''Unreleased structure''' The entry 6nwl is ON HOLD Authors: Liu, X., Ortlund, E.A. Description: Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex ...

New page

'''Unreleased structure'''

The entry 6nwl is ON HOLD

Authors: Liu, X., Ortlund, E.A.

Description: Structure of the Ancestral Glucocorticoid Receptor 2 ligand binding domain in complex with hydrocortisone and PGC1a coregulator fragment
[[Category: Unreleased Structures]]
[[Category: Liu, X]]
[[Category: Ortlund, E.A]]