7jup - Revision history

OCA at 14:53, 6 March 2024

OCA — Wed, 06 Mar 2024 14:53:57 GMT

←Older revision		Revision as of 14:53, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='7jup' size='340' side='right'caption='[[7jup]], [[Resolution\|resolution]] 3.05Å' scene=''>		<StructureSection load='7jup' size='340' side='right'caption='[[7jup]], [[Resolution\|resolution]] 3.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7jup]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JUP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7jup]] 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=7JUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JUP FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VKM:1-({3-[(3R,5R)-5-(4-fluorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1,7-dihydro-6H-purin-6-one'>VKM</scene>~~</td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 3.05Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TRPA1, ANKTM1 ([https://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=VKM:1-({3-[(3R,5R)-5-(4-fluorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1,7-dihydro-6H-purin-6-one'>VKM</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=7jup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jup OCA], [https://pdbe.org/7jup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jup RCSB], [https://www.ebi.ac.uk/pdbsum/7jup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jup 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=7jup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jup OCA], [https://pdbe.org/7jup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jup RCSB], [https://www.ebi.ac.uk/pdbsum/7jup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jup ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN]] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry.	+	[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry.
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN]] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8]<ref>PMID:20547126</ref> <ref>PMID:25389312</ref> <ref>PMID:25855297</ref>	+	[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8]<ref>PMID:20547126</ref> <ref>PMID:25389312</ref> <ref>PMID:25855297</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 A, revealing the binding site and mechanism of action for this class of antagonists.	+
-		+
-	Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.,Terrett JA, Chen H, Shore DG, Villemure E, Larouche-Gauthier R, Dery M, Beaumier F, Constantineau-Forget L, Grand-Maitre C, Lepissier L, Ciblat S, Sturino C, Chen Y, Hu B, Lu A, Wang Y, Cridland AP, Ward SI, Hackos DH, Reese RM, Shields SD, Chen J, Balestrini A, Riol-Blanco L, Lee WP, Liu J, Suto E, Wu X, Zhang J, Ly JQ, La H, Johnson K, Baumgardner M, Chou KJ, Rohou A, Rouge L, Safina BS, Magnuson S, Volgraf M J Med Chem. 2021 Mar 22. doi: 10.1021/acs.jmedchem.0c02023. PMID:33749283<ref>PMID:33749283</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7jup" 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: Rohou, A]]	+	[[Category: Rohou A]]
-	[[Category: Rouge, L]]	+	[[Category: Rouge L]]
-	~~[[Category: Agonist]]~~	+
-	~~[[Category: Channel]]~~	+
-	~~[[Category: Membrane protein]]~~	+
-	~~[[Category: Membrane protein-antagonist complex]]~~	+
-	~~[[Category: Trpa1~~]]	+

OCA at 08:33, 21 April 2021

OCA — Wed, 21 Apr 2021 08:33:54 GMT

←Older revision		Revision as of 08:33, 21 April 2021
Line 1:		Line 1:

	==Structure of human TRPA1 in complex with antagonist compound 21==		==Structure of human TRPA1 in complex with antagonist compound 21==
-	<StructureSection load='7jup' size='340' side='right'caption='[[7jup]]' scene=''>	+	<StructureSection load='7jup' size='340' side='right'caption='[[7jup]], [[Resolution\|resolution]] 3.05Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JUP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7jup]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JUP FirstGlance]. <br>
-	</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=7jup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jup OCA], [https://pdbe.org/7jup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jup RCSB], [https://www.ebi.ac.uk/pdbsum/7jup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jup ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VKM:1-({3-[(3R,5R)-5-(4-fluorophenyl)oxolan-3-yl]-1,2,4-oxadiazol-5-yl}methyl)-7-methyl-1,7-dihydro-6H-purin-6-one'>VKM</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TRPA1, ANKTM1 ([https://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=7jup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jup OCA], [https://pdbe.org/7jup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jup RCSB], [https://www.ebi.ac.uk/pdbsum/7jup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jup ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN]] Familial episodic pain syndrome with predominantly upper body involvement. The disease is caused by mutations affecting the gene represented in this entry.
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/TRPA1_HUMAN TRPA1_HUMAN]] Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as an ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).[UniProtKB:Q8BLA8]<ref>PMID:20547126</ref> <ref>PMID:25389312</ref> <ref>PMID:25855297</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium-permeable ion channel highly expressed in the primary sensory neurons functioning as a polymodal sensor for exogenous and endogenous stimuli and has generated widespread interest as a target for inhibition due to its implication in neuropathic pain and respiratory disease. Herein, we describe the optimization of a series of potent, selective, and orally bioavailable TRPA1 small molecule antagonists, leading to the discovery of a novel tetrahydrofuran-based linker. Given the balance of physicochemical properties and strong in vivo target engagement in a rat AITC-induced pain assay, compound 20 was progressed into a guinea pig ovalbumin asthma model where it exhibited significant dose-dependent reduction of inflammatory response. Furthermore, the structure of the TRPA1 channel bound to compound 21 was determined via cryogenic electron microscopy to a resolution of 3 A, revealing the binding site and mechanism of action for this class of antagonists.
		+
		+	Tetrahydrofuran-Based Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists: Ligand-Based Discovery, Activity in a Rodent Asthma Model, and Mechanism-of-Action via Cryogenic Electron Microscopy.,Terrett JA, Chen H, Shore DG, Villemure E, Larouche-Gauthier R, Dery M, Beaumier F, Constantineau-Forget L, Grand-Maitre C, Lepissier L, Ciblat S, Sturino C, Chen Y, Hu B, Lu A, Wang Y, Cridland AP, Ward SI, Hackos DH, Reese RM, Shields SD, Chen J, Balestrini A, Riol-Blanco L, Lee WP, Liu J, Suto E, Wu X, Zhang J, Ly JQ, La H, Johnson K, Baumgardner M, Chou KJ, Rohou A, Rouge L, Safina BS, Magnuson S, Volgraf M J Med Chem. 2021 Mar 22. doi: 10.1021/acs.jmedchem.0c02023. PMID:33749283<ref>PMID:33749283</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7jup" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Rohou A]]	+	[[Category: Rohou, A]]
-	[[Category: Rouge L]]	+	[[Category: Rouge, L]]
		+	[[Category: Agonist]]
		+	[[Category: Channel]]
		+	[[Category: Membrane protein]]
		+	[[Category: Membrane protein-antagonist complex]]
		+	[[Category: Trpa1]]

OCA at 10:33, 31 March 2021

OCA — Wed, 31 Mar 2021 10:33:29 GMT

←Older revision		Revision as of 10:33, 31 March 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7jup ~~is ON HOLD~~	+	==Structure of human TRPA1 in complex with antagonist compound 21==
-		+	<StructureSection load='7jup' size='340' side='right'caption='[[7jup]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JUP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JUP FirstGlance]. <br>
-	~~Description~~:	+	</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=7jup FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jup OCA], [https://pdbe.org/7jup PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jup RCSB], [https://www.ebi.ac.uk/pdbsum/7jup PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jup ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Rohou A]]
		+	[[Category: Rouge L]]

OCA: Protected "7jup" [edit=sysop:move=sysop]

OCA — Wed, 26 Aug 2020 09:43:44 GMT

Protected "7jup" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:43, 26 August 2020

OCA: New page: '''Unreleased structure''' The entry 7jup is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 26 Aug 2020 09:43:42 GMT

New page: '''Unreleased structure''' The entry 7jup is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7jup is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]