5vb6 - Revision history

OCA at 14:32, 6 March 2024

2024-03-06T14:32:00Z

←Older revision		Revision as of 14:32, 6 March 2024
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	==X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with an inverse agonist and SRC2 peptide==		==X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with an inverse agonist and SRC2 peptide==
-	<StructureSection load='5vb6' size='340' side='right' caption='[[5vb6]], [[Resolution\|resolution]] 2.04Å' scene=''>	+	<StructureSection load='5vb6' size='340' side='right'caption='[[5vb6]], [[Resolution\|resolution]] 2.04Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5vb6]] is a 1 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=5VB6 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5VB6 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5vb6]] is a 1 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=5VB6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5VB6 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=927:N-{3-[(3-methylbut-2-en-1-yl){methyl[trans-4-(pyridin-4-yl)cyclohexyl]carbamoyl}amino]phenyl}benzamide'>927</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 2.041Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vb7\|5vb7]], [[5vb5\|5vb5]], [[5vb3\|5vb3]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=927:N-{3-[(3-methylbut-2-en-1-yl){methyl[trans-4-(pyridin-4-yl)cyclohexyl]carbamoyl}amino]phenyl}benzamide'>927</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([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'>[https://proteopedia.org/fgij/fg.htm?mol=5vb6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vb6 OCA], [https://pdbe.org/5vb6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5vb6 RCSB], [https://www.ebi.ac.uk/pdbsum/5vb6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5vb6 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=5vb6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vb6 OCA], [~~http~~://pdbe.org/5vb6 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5vb6 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5vb6 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5vb6 ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Disease ==
		+	[https://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/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.	+	[https://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/RORG_HUMAN RORG_HUMAN] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The nuclear receptor retinoid acid receptor-related orphan receptor gammat (RORgammat) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORgammat has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORgammat. Here, we report the crystal structures for the ligand-binding domain of RORgammat in both apo and ligand-bound states. We show that apo RORgammat adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORgammat in the active state in the absence of a ligand. The structures of ligand-bound RORgammat reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORgammat toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.	+
-		+
-	Structural studies unravel the active conformation of apo RORgammat nuclear receptor and a common inverse agonism of two diverse classes of RORgammat inhibitors.,Li X, Anderson M, Collin D, Muegge I, Wan J, Brennan D, Kugler S, Terenzio D, Kennedy C, Lin S, Labadia ME, Cook B, Hughes R, Farrow NA J Biol Chem. 2017 Jul 14;292(28):11618-11630. doi: 10.1074/jbc.M117.789024. Epub , 2017 May 25. PMID:28546429<ref>PMID:28546429</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5vb6" style="background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Li, X~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Nuclear hormone receptor]]~~	+	[[Category: Li X]]
-	~~[[Category: Nuclear receptor]]~~	+
-	~~[[Category: Transcription~~]]	+

OCA at 06:13, 16 November 2017

2017-11-16T06:13:09Z

←Older revision		Revision as of 06:13, 16 November 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5vb6 is ~~ON HOLD until Paper~~ Publication	+	==X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with an inverse agonist and SRC2 peptide==
		+	<StructureSection load='5vb6' size='340' side='right' caption='[[5vb6]], [[Resolution\|resolution]] 2.04Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5vb6]] is a 1 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=5VB6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5VB6 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=927:N-{3-[(3-methylbut-2-en-1-yl){methyl[trans-4-(pyridin-4-yl)cyclohexyl]carbamoyl}amino]phenyl}benzamide'>927</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5vb7\|5vb7]], [[5vb5\|5vb5]], [[5vb3\|5vb3]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RORC, NR1F3, RORG, RZRG ([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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5vb6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5vb6 OCA], [http://pdbe.org/5vb6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5vb6 RCSB], [http://www.ebi.ac.uk/pdbsum/5vb6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5vb6 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/RORG_HUMAN RORG_HUMAN]] Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The nuclear receptor retinoid acid receptor-related orphan receptor gammat (RORgammat) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORgammat has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we previously identified several classes of inverse agonists for RORgammat. Here, we report the crystal structures for the ligand-binding domain of RORgammat in both apo and ligand-bound states. We show that apo RORgammat adopts an active conformation capable of recruiting coactivator peptides and present a detailed analysis of the structural determinants that stabilize helix 12 (H12) of RORgammat in the active state in the absence of a ligand. The structures of ligand-bound RORgammat reveal that binding of the inverse agonists disrupts critical interactions that stabilize H12. This destabilizing effect is supported by ab initio calculations and experimentally by a normalized crystallographic B-factor analysis. Of note, the H12 destabilization in the active state shifts the conformational equilibrium of RORgammat toward an inactive state, which underlies the molecular mechanism of action for the inverse agonists reported here. Our findings highlight that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from agonists to inverse agonists.

-	~~Authors: Li~~, X.	+	Structural studies unravel the active conformation of apo RORgammat nuclear receptor and a common inverse agonism of two diverse classes of RORgammat inhibitors.,Li X, Anderson M, Collin D, Muegge I, Wan J, Brennan D, Kugler S, Terenzio D, Kennedy C, Lin S, Labadia ME, Cook B, Hughes R, Farrow NA J Biol Chem. 2017 Jul 14;292(28):11618-11630. doi: 10.1074/jbc.M117.789024. Epub , 2017 May 25. PMID:28546429<ref>PMID:28546429</ref>

-	~~Description: X-ray co-structure~~ of ~~nuclear receptor ROR~~-~~gammat Ligand Binding Domain with an inverse agonist and SRC2 peptide~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5vb6" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Li, X]]		[[Category: Li, X]]
		+	[[Category: Nuclear hormone receptor]]
		+	[[Category: Nuclear receptor]]
		+	[[Category: Transcription]]

OCA: Protected "5vb6" [edit=sysop:move=sysop]

2017-04-05T11:53:04Z

Protected "5vb6" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:53, 5 April 2017

OCA: New page: '''Unreleased structure''' The entry 5vb6 is ON HOLD until Paper Publication Authors: Li, X. Description: X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with a...

2017-04-05T11:53:03Z

New page: '''Unreleased structure''' The entry 5vb6 is ON HOLD until Paper Publication Authors: Li, X. Description: X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with a...

New page

'''Unreleased structure'''

The entry 5vb6 is ON HOLD until Paper Publication

Authors: Li, X.

Description: X-ray co-structure of nuclear receptor ROR-gammat Ligand Binding Domain with an inverse agonist and SRC2 peptide
[[Category: Unreleased Structures]]
[[Category: Li, X]]