6nw2 - Revision history

OCA at 14:49, 13 March 2024

2024-03-13T14:49:12Z

←Older revision		Revision as of 14:49, 13 March 2024
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	<StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nw2]] 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=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nw2]] 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=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</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]] 2Å</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=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</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=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [https://pdbe.org/6nw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [https://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 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=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [~~http~~://pdbe.org/6nw2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 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 ==~~	+
-	Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.	+

-	~~Potent and selective inhibitors of receptor-interacting~~ protein kinase 1 that lack an aromatic back pocket group.,Hamilton GL, Chen H, Deshmukh G, Eigenbrot C, Fong R, Johnson A, Kohli PB, Lupardus PJ, Liederer BM, Ramaswamy S, Wang H, Wang J, Xu Z, Zhu Y, Vucic D, Patel S Bioorg Med Chem Lett. 2019 Apr 11. pii: S0960-894X(19)30223-9. doi:, 10.1016/~~j.bmcl.2019.04.014. PMID:31000154<ref>PMID:31000154</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 6nw2" 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: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Fong R]]
-	[[Category: Fong, R]]	+	[[Category: Lupardus PJ]]
-	[[Category: Lupardus~~, P J]]~~	+
-	~~[[Category: Immune system]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Rip]]~~	+
-	~~[[Category: Rip1]]~~	+
-	~~[[Category: Rip1k ripk1]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:22, 21 May 2019

2019-05-21T08:22:49Z

←Older revision		Revision as of 08:22, 21 May 2019
Line 3:		Line 3:
	<StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution\|resolution]] 2.00Å' scene=''>		<StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution\|resolution]] 2.00Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6nw2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6nw2]] 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=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</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='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=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [http://pdbe.org/6nw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 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=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [http://pdbe.org/6nw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 ProSAT]</span></td></tr>
Line 23:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]

OCA at 08:55, 1 May 2019

2019-05-01T08:55:24Z

←Older revision		Revision as of 08:55, 1 May 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6nw2 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Structure of human RIPK1 kinase domain in complex with compound 11==
		+	<StructureSection load='6nw2' size='340' side='right'caption='[[6nw2]], [[Resolution\|resolution]] 2.00Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6nw2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NW2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NW2 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L4Y:(5R)-5-methyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxamide'>L4Y</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6nw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nw2 OCA], [http://pdbe.org/6nw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6nw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nw2 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 ==
		+	Receptor-interacting protein kinase 1 (RIPK1), a key component of the cellular necroptosis pathway, has gained recognition as an important therapeutic target. Pharmacologic inhibition or genetic inactivation of RIPK1 has shown promise in animal models of disease ranging from acute ischemic conditions, chronic inflammation, and neurodegeneration. We present here a class of RIPK1 inhibitors that is distinguished by a lack of a lipophilic aromatic group present in most literature inhibitors that typically occupies a hydrophobic back pocket of the protein active site. Despite not having this ubiquitous feature of many known RIPK1 inhibitors, we were able to obtain compounds with good potency, kinase selectivity, and pharmacokinetic properties in rats. The use of the lipophilic yet metabolically stable pentafluoroethyl group was critical to balancing the potency and properties of optimized analogs.

-	~~Authors: Fong~~, R., Lupardus, P.J.	+	Potent and selective inhibitors of receptor-interacting protein kinase 1 that lack an aromatic back pocket group.,Hamilton GL, Chen H, Deshmukh G, Eigenbrot C, Fong R, Johnson A, Kohli PB, Lupardus PJ, Liederer BM, Ramaswamy S, Wang H, Wang J, Xu Z, Zhu Y, Vucic D, Patel S Bioorg Med Chem Lett. 2019 Apr 11. pii: S0960-894X(19)30223-9. doi:, 10.1016/j.bmcl.2019.04.014. PMID:31000154<ref>PMID:31000154</ref>

-	~~Description: Structure~~ of ~~human RIPK1 kinase domain in complex with compound 11~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Lupardus, P.J~~]]	+	<div class="pdbe-citations 6nw2" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Fong, R]]		[[Category: Fong, R]]
		+	[[Category: Lupardus, P J]]
		+	[[Category: Immune system]]
		+	[[Category: Kinase]]
		+	[[Category: Rip]]
		+	[[Category: Rip1]]
		+	[[Category: Rip1k ripk1]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 04:32, 3 April 2019

2019-04-03T04:32:12Z

←Older revision		Revision as of 04:32, 3 April 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6nw2 is ON HOLD	+	The entry 6nw2 is ON HOLD until Paper Publication

	Authors: Fong, R., Lupardus, P.J.		Authors: Fong, R., Lupardus, P.J.

OCA: Protected "6nw2" [edit=sysop:move=sysop]

2019-02-13T07:51:12Z

Protected "6nw2" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:51, 13 February 2019

OCA: New page: '''Unreleased structure''' The entry 6nw2 is ON HOLD Authors: Fong, R., Lupardus, P.J. Description: Structure of human RIPK1 kinase domain in complex with compound 11 [[Category: Unrel...

2019-02-13T07:51:10Z

New page: '''Unreleased structure''' The entry 6nw2 is ON HOLD Authors: Fong, R., Lupardus, P.J. Description: Structure of human RIPK1 kinase domain in complex with compound 11 [[Category: Unrel...

New page

'''Unreleased structure'''

The entry 6nw2 is ON HOLD

Authors: Fong, R., Lupardus, P.J.

Description: Structure of human RIPK1 kinase domain in complex with compound 11
[[Category: Unreleased Structures]]
[[Category: Lupardus, P.J]]
[[Category: Fong, R]]