5nti - Revision history

OCA at 07:27, 1 May 2024

OCA — Wed, 01 May 2024 07:27:32 GMT

←Older revision		Revision as of 07:27, 1 May 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[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.		[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 T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-gamma (RORgammat) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORgammat inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORgammat agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORgammat modulators.
-
-	Structural States of RORgammat: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds.,Kallen J, Izaac A, Be C, Arista L, Orain D, Kaupmann K, Guntermann C, Hoegenauer K, Hintermann S ChemMedChem. 2017 Jul 6;12(13):1014-1021. doi: 10.1002/cmdc.201700278. Epub 2017 , Jun 20. PMID:28590087<ref>PMID:28590087</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 5nti" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 12:07, 22 November 2023

OCA — Wed, 22 Nov 2023 12:07:36 GMT

←Older revision		Revision as of 12:07, 22 November 2023
Line 3:		Line 3:
	<StructureSection load='5nti' size='340' side='right'caption='[[5nti]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='5nti' size='340' side='right'caption='[[5nti]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5nti]] is a 8 chain structure with sequence from [~~http://en.wikipedia.org/wiki/ ] and [http~~://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NTI OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5NTI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5nti]] is a 8 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=5NTI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NTI FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</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]] 2.4Å</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=5nti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nti OCA], [~~http~~://pdbe.org/5nti PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5nti RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5nti PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5nti ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</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=5nti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nti OCA], [https://pdbe.org/5nti PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nti RCSB], [https://www.ebi.ac.uk/pdbsum/5nti PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nti ProSAT]</span></td></tr>
	</table>		</table>
	== 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/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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 25:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Kallen, J]]	+	[[Category: Kallen J]]
-	~~[[Category: Agonist]]~~	+
-	~~[[Category: Ligand-binding domain]]~~	+
-	~~[[Category: Nuclear hormone receptor]]~~	+
-	~~[[Category: Signaling protein~~]]	+

OCA at 12:11, 26 August 2020

OCA — Wed, 26 Aug 2020 12:11:56 GMT

←Older revision		Revision as of 12:11, 26 August 2020
Line 1:		Line 1:

	==Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds==		==Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds==
-	<StructureSection load='5nti' size='340' side='right' caption='[[5nti]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='5nti' size='340' side='right'caption='[[5nti]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5nti]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NTI OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5NTI FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5nti]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NTI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5NTI FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</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=5nti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nti OCA], [http://pdbe.org/5nti PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nti RCSB], [http://www.ebi.ac.uk/pdbsum/5nti PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nti 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=5nti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nti OCA], [http://pdbe.org/5nti PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nti RCSB], [http://www.ebi.ac.uk/pdbsum/5nti PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nti ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 23:		Line 23:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
	[[Category: Kallen, J]]		[[Category: Kallen, J]]
	[[Category: Agonist]]		[[Category: Agonist]]

OCA at 16:47, 20 October 2017

OCA — Fri, 20 Oct 2017 16:47:25 GMT

←Older revision		Revision as of 16:47, 20 October 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5nti is ~~ON HOLD until Paper~~ Publication	+	==Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds==
		+	<StructureSection load='5nti' size='340' side='right' caption='[[5nti]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5nti]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NTI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NTI FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C3S:CHOLEST-5-EN-3-YL+HYDROGEN+SULFATE'>C3S</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=5nti FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nti OCA], [http://pdbe.org/5nti PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nti RCSB], [http://www.ebi.ac.uk/pdbsum/5nti PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nti 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 T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-gamma (RORgammat) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORgammat inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORgammat agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co-crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORgammat modulators.

-	~~Authors~~: ~~Kallen~~, J.	+	Structural States of RORgammat: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds.,Kallen J, Izaac A, Be C, Arista L, Orain D, Kaupmann K, Guntermann C, Hoegenauer K, Hintermann S ChemMedChem. 2017 Jul 6;12(13):1014-1021. doi: 10.1002/cmdc.201700278. Epub 2017 , Jun 20. PMID:28590087<ref>PMID:28590087</ref>

-	~~Description: Structural states~~ of ~~RORgt: X-ray elucidation~~ of ~~molecular mechanisms and binding interactions for natural and synthetic compounds~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5nti" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Kallen, J]]		[[Category: Kallen, J]]
		+	[[Category: Agonist]]
		+	[[Category: Ligand-binding domain]]
		+	[[Category: Nuclear hormone receptor]]
		+	[[Category: Signaling protein]]

OCA at 09:20, 10 May 2017

OCA — Wed, 10 May 2017 09:20:02 GMT

←Older revision		Revision as of 09:20, 10 May 2017
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5nti is ON HOLD	+	The entry 5nti is ON HOLD until Paper Publication

	Authors: Kallen, J.		Authors: Kallen, J.

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

OCA — Thu, 04 May 2017 09:42:31 GMT

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

←Older revision

Revision as of 09:42, 4 May 2017

OCA: New page: '''Unreleased structure''' The entry 5nti is ON HOLD Authors: Kallen, J. Description: Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for...

OCA — Thu, 04 May 2017 09:42:30 GMT

New page: '''Unreleased structure''' The entry 5nti is ON HOLD Authors: Kallen, J. Description: Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for...

New page

'''Unreleased structure'''

The entry 5nti is ON HOLD

Authors: Kallen, J.

Description: Structural states of RORgt: X-ray elucidation of molecular mechanisms and binding interactions for natural and synthetic compounds
[[Category: Unreleased Structures]]
[[Category: Kallen, J]]