6o3z - Revision history

OCA at 14:50, 13 March 2024

OCA — Wed, 13 Mar 2024 14:50:26 GMT

←Older revision		Revision as of 14:50, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6o3z]] 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=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6o3z]] 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=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [~~http~~://pdbe.org/6o3z PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z ProSAT]</span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [https://pdbe.org/6o3z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [https://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z ProSAT]</span></td></tr>
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[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.
-	~~The retinoic acid receptor-related orphan~~ nuclear receptor ~~gammat (RORgammat)~~, ~~a promising therapeutic target, is a major transcription factor~~ of ~~genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22,~~ and ~~IL-23R. On~~ the ~~basis of the X-ray cocrystal structure~~ of ~~RORgammat with 1a~~, ~~an analogue of the known piperazine RORgammat inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORgammat inverse agonist~~. ~~Structure-activity relationship studies on 3a, focusing on the treatment~~ of ~~its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-~~(~~7-methyl-8-(((2S,4S~~)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)b utanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORgammat inhibitory activity and a favorable pharmacokinetic profile. ~~Moreover,~~ the ~~in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine~~ expression ~~model revealed its robust and dose-dependent inhibitory effect on IL-17A production.~~	+
-		+
-	~~Discovery~~ of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORgammat Inverse Agonists.,Nakajima R, Oono H, Sugiyama S, Matsueda Y, Ida T, Kakuda S, Hirata J, Baba A, Makino A, Matsuyama R, White RD, Wurz RRho, Shin Y, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S ACS Med Chem Lett. 2020 Feb 27;11(4):528-534. doi:, 10.1021/acsmedchemlett.9b00649. eCollection 2020 Apr 9. PMID:32292560<ref>PMID:32292560</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database~~ of the U.~~S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6o3z" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Min, X]]	+	[[Category: Min X]]
-	[[Category: Wang, Z]]	+	[[Category: Wang Z]]
-	~~[[Category: Protein binding]]~~	+
-	~~[[Category: Retinoic acid receptor-related orphan receptor gt]]~~	+
-	~~[[Category: Rorgt~~]]	+

OCA at 07:00, 29 April 2020

OCA — Wed, 29 Apr 2020 07:00:49 GMT

←Older revision		Revision as of 07:00, 29 April 2020
Line 3:		Line 3:
	<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6o3z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6o3z]] 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=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [http://pdbe.org/6o3z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [http://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z 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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [http://pdbe.org/6o3z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [http://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The retinoic acid receptor-related orphan nuclear receptor gammat (RORgammat), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORgammat with 1a, an analogue of the known piperazine RORgammat inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORgammat inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)b utanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORgammat inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.
		+
		+	Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORgammat Inverse Agonists.,Nakajima R, Oono H, Sugiyama S, Matsueda Y, Ida T, Kakuda S, Hirata J, Baba A, Makino A, Matsuyama R, White RD, Wurz RRho, Shin Y, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S ACS Med Chem Lett. 2020 Feb 27;11(4):528-534. doi:, 10.1021/acsmedchemlett.9b00649. eCollection 2020 Apr 9. PMID:32292560<ref>PMID:32292560</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6o3z" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Min, X]]		[[Category: Min, X]]

OCA at 06:43, 4 March 2020

OCA — Wed, 04 Mar 2020 06:43:45 GMT

←Older revision		Revision as of 06:43, 4 March 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6o3z ~~is ON HOLD until Paper Publication~~	+	==Crystal structure of RORgt with 3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide (compound 1)==
-		+	<StructureSection load='6o3z' size='340' side='right'caption='[[6o3z]], [[Resolution\|resolution]] 2.40Å' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6o3z]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6O3Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O3Z FirstGlance]. <br>
-	~~Description~~:	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LKY:3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide'>LKY</scene></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	<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=6o3z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o3z OCA], [http://pdbe.org/6o3z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o3z RCSB], [http://www.ebi.ac.uk/pdbsum/6o3z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o3z ProSAT]</span></td></tr>
		+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Min, X]]
		+	[[Category: Wang, Z]]
		+	[[Category: Protein binding]]
		+	[[Category: Retinoic acid receptor-related orphan receptor gt]]
		+	[[Category: Rorgt]]

OCA at 04:53, 23 October 2019

OCA — Wed, 23 Oct 2019 04:53:38 GMT

←Older revision		Revision as of 04:53, 23 October 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6o3z is ON HOLD until ~~Feb 27 2021~~	+	The entry 6o3z is ON HOLD until Paper Publication

	Authors:		Authors:

OCA at 05:55, 20 March 2019

OCA — Wed, 20 Mar 2019 05:55:56 GMT

←Older revision		Revision as of 05:55, 20 March 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6o3z is ON HOLD	+	The entry 6o3z is ON HOLD until Feb 27 2021

	Authors:		Authors:

OCA: Protected "6o3z" [edit=sysop:move=sysop]

OCA — Wed, 06 Mar 2019 05:45:50 GMT

Protected "6o3z" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:45, 6 March 2019

OCA: New page: '''Unreleased structure''' The entry 6o3z is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 06 Mar 2019 05:45:48 GMT

New page: '''Unreleased structure''' The entry 6o3z is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6o3z is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]