5tx5 - Revision history

OCA at 14:23, 6 March 2024

OCA — Wed, 06 Mar 2024 14:23:57 GMT

←Older revision		Revision as of 14:23, 6 March 2024
Line 1:		Line 1:

	==Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772==		==Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772==
-	<StructureSection load='5tx5' size='340' side='right' caption='[[5tx5]], [[Resolution\|resolution]] 2.56Å' scene=''>	+	<StructureSection load='5tx5' size='340' side='right'caption='[[5tx5]], [[Resolution\|resolution]] 2.56Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5tx5]] 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=5TX5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5TX5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5tx5]] 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=5TX5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TX5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7MJ:3-benzyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-5-carboxamide'>7MJ</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]] 2.56Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RIPK1, RIP, RIP1 ([http://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=7MJ:3-benzyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-5-carboxamide'>7MJ</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5tx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tx5 OCA], [https://pdbe.org/5tx5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tx5 RCSB], [https://www.ebi.ac.uk/pdbsum/5tx5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tx5 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=5tx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tx5 OCA], [~~http~~://pdbe.org/5tx5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5tx5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5tx5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5tx5 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/RIPK1_HUMAN RIPK1_HUMAN]] Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref>	+	[https://www.uniprot.org/uniprot/RIPK1_HUMAN RIPK1_HUMAN] Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.	+

-	Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.,Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X, Eidam PM, Finger JN, Hoffman SJ, Kang J, Kasparcova V, King BW, Lehr R, Lan Y, Leister LK, Lich JD, MacDonald TT, Miller NA, Ouellette MT, Pao CS, Rahman A, Reilly MA, Rendina AR, Rivera EJ, Schaeffer MC, Sehon CA, Singhaus RR, Sun HH, Swift BA, Totoritis RD, Vossenkamper A, Ward P, Wisnoski DD, Zhang D, Marquis RW, Gough PJ, Bertin J J Med Chem. 2017 Feb 23;60(4):1247-1261. doi: 10.1021/acs.jmedchem.6b01751. Epub , 2017 Feb 10. PMID:28151659<ref>PMID:28151659</ref>	+	==See Also==
-		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
-	~~From MEDLINE®~~/~~PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5tx5" style="background-color:#fffaf0;"><~~/~~div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific serine/threonine protein kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Campobasso, N]]	+	[[Category: Campobasso N]]
-	[[Category: Thrope, J]]	+	[[Category: Thrope J]]
-	[[Category: Ward, P]]	+	[[Category: Ward P]]
-	~~[[Category: Kinase domain inhibitor necrosis]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 06:39, 16 November 2017

OCA — Thu, 16 Nov 2017 06:39:07 GMT

←Older revision		Revision as of 06:39, 16 November 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5tx5 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772==
		+	<StructureSection load='5tx5' size='340' side='right' caption='[[5tx5]], [[Resolution\|resolution]] 2.56Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5tx5]] 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=5TX5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TX5 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7MJ:3-benzyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-1H-1,2,4-triazole-5-carboxamide'>7MJ</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">RIPK1, RIP, RIP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5tx5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tx5 OCA], [http://pdbe.org/5tx5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tx5 RCSB], [http://www.ebi.ac.uk/pdbsum/5tx5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tx5 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/RIPK1_HUMAN RIPK1_HUMAN]] Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage. Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor. Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules. Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death. RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex.<ref>PMID:11101870</ref> <ref>PMID:19524513</ref> <ref>PMID:19524512</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

-	~~Authors: Campobasso~~, N., ~~Ward~~, P., ~~Thrope~~, J.	+	Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.,Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, Capriotti CA, Cox JA, Dare L, Dong X, Eidam PM, Finger JN, Hoffman SJ, Kang J, Kasparcova V, King BW, Lehr R, Lan Y, Leister LK, Lich JD, MacDonald TT, Miller NA, Ouellette MT, Pao CS, Rahman A, Reilly MA, Rendina AR, Rivera EJ, Schaeffer MC, Sehon CA, Singhaus RR, Sun HH, Swift BA, Totoritis RD, Vossenkamper A, Ward P, Wisnoski DD, Zhang D, Marquis RW, Gough PJ, Bertin J J Med Chem. 2017 Feb 23;60(4):1247-1261. doi: 10.1021/acs.jmedchem.6b01751. Epub , 2017 Feb 10. PMID:28151659<ref>PMID:28151659</ref>

-	~~Description: Rip1 Kinase ( flag 1-294~~, ~~C34A, C127A, C233A, C240A) with GSK772~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5tx5" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Campobasso, N]]		[[Category: Campobasso, N]]
	[[Category: Thrope, J]]		[[Category: Thrope, J]]
	[[Category: Ward, P]]		[[Category: Ward, P]]
		+	[[Category: Kinase domain inhibitor necrosis]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 13:51, 9 March 2017

OCA — Thu, 09 Mar 2017 13:51:15 GMT

←Older revision		Revision as of 13:51, 9 March 2017
Line 7:		Line 7:
	Description: Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772		Description: Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Thrope, J]]
	[[Category: Campobasso, N]]		[[Category: Campobasso, N]]
		+	[[Category: Thrope, J]]
	[[Category: Ward, P]]		[[Category: Ward, P]]

OCA at 20:10, 22 December 2016

OCA — Thu, 22 Dec 2016 20:10:03 GMT

←Older revision		Revision as of 20:10, 22 December 2016
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5tx5 is ON HOLD	+	The entry 5tx5 is ON HOLD until Paper Publication

	Authors: Campobasso, N., Ward, P., Thrope, J.		Authors: Campobasso, N., Ward, P., Thrope, J.

OCA: Protected "5tx5" [edit=sysop:move=sysop]

OCA — Fri, 09 Dec 2016 18:00:10 GMT

Protected "5tx5" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:00, 9 December 2016

OCA: New page: '''Unreleased structure''' The entry 5tx5 is ON HOLD Authors: Campobasso, N., Ward, P., Thrope, J. Description: Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772 [[Categ...

OCA — Fri, 09 Dec 2016 18:00:09 GMT

New page: '''Unreleased structure''' The entry 5tx5 is ON HOLD Authors: Campobasso, N., Ward, P., Thrope, J. Description: Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772 [[Categ...

New page

'''Unreleased structure'''

The entry 5tx5 is ON HOLD

Authors: Campobasso, N., Ward, P., Thrope, J.

Description: Rip1 Kinase ( flag 1-294, C34A, C127A, C233A, C240A) with GSK772
[[Category: Unreleased Structures]]
[[Category: Thrope, J]]
[[Category: Campobasso, N]]
[[Category: Ward, P]]