7rsp - Revision history

OCA at 14:58, 13 March 2024

2024-03-13T14:58:52Z

←Older revision		Revision as of 14:58, 13 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7rsp]] 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=7RSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RSP FirstGlance]. <br>		<table><tr><td colspan='2'>[[7rsp]] 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=7RSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RSP FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7IK:(7R,8R)-2-[(3R)-3-methylmorpholin-4-yl]-7-(propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one'>7IK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 1.67Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7IK:(7R,8R)-2-[(3R)-3-methylmorpholin-4-yl]-7-(propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one'>7IK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7rsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rsp OCA], [https://pdbe.org/7rsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rsp RCSB], [https://www.ebi.ac.uk/pdbsum/7rsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rsp 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=7rsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rsp OCA], [https://pdbe.org/7rsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rsp RCSB], [https://www.ebi.ac.uk/pdbsum/7rsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rsp ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN]] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>	+	[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.	+
-		+
-	Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.,Hu DX, Patel S, Chen H, Wang S, Staben ST, Dimitrova YN, Wallweber HA, Lee JY, Chan GKY, Sneeringer CJ, Prangley MS, Moffat JG, Wu KC, Schutt LK, Salphati L, Pang J, McNamara E, Huang H, Chen Y, Wang Y, Zhao W, Lim J, Murthy A, Siu M J Med Chem. 2021 Nov 15. doi: 10.1021/acs.jmedchem.1c01180. PMID:34779204<ref>PMID:34779204</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7rsp" style="background-color:#fffaf0;"></div~~>	+

	==See Also==		==See Also==

OCA at 07:03, 14 September 2022

2022-09-14T07:03:12Z

←Older revision		Revision as of 07:03, 14 September 2022
Line 1:		Line 1:

	==Structure of the VPS34 kinase domain with compound 14==		==Structure of the VPS34 kinase domain with compound 14==
-	<StructureSection load='7rsp' size='340' side='right'caption='[[7rsp]]' scene=''>	+	<StructureSection load='7rsp' size='340' side='right'caption='[[7rsp]], [[Resolution\|resolution]] 1.67Å' 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=7RSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RSP FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7rsp]] 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=7RSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RSP 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=7rsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rsp OCA], [https://pdbe.org/7rsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rsp RCSB], [https://www.ebi.ac.uk/pdbsum/7rsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rsp 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=7IK:(7R,8R)-2-[(3R)-3-methylmorpholin-4-yl]-7-(propan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one'>7IK</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7rsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rsp OCA], [https://pdbe.org/7rsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rsp RCSB], [https://www.ebi.ac.uk/pdbsum/7rsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rsp ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN]] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.
		+
		+	Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors.,Hu DX, Patel S, Chen H, Wang S, Staben ST, Dimitrova YN, Wallweber HA, Lee JY, Chan GKY, Sneeringer CJ, Prangley MS, Moffat JG, Wu KC, Schutt LK, Salphati L, Pang J, McNamara E, Huang H, Chen Y, Wang Y, Zhao W, Lim J, Murthy A, Siu M J Med Chem. 2021 Nov 15. doi: 10.1021/acs.jmedchem.1c01180. PMID:34779204<ref>PMID:34779204</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7rsp" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphoinositide 3-kinase 3D structures\|Phosphoinositide 3-kinase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Chan GKY]]		[[Category: Chan GKY]]

OCA at 12:38, 24 November 2021

2021-11-24T12:38:34Z

←Older revision		Revision as of 12:38, 24 November 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7rsp is ~~ON HOLD until Paper Publication~~	+	==Structure of the VPS34 kinase domain with compound 14==
-		+	<StructureSection load='7rsp' size='340' side='right'caption='[[7rsp]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RSP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RSP 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=7rsp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rsp OCA], [https://pdbe.org/7rsp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rsp RCSB], [https://www.ebi.ac.uk/pdbsum/7rsp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rsp ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Chan GKY]]
		+	[[Category: Chen H]]
		+	[[Category: Chen Y]]
		+	[[Category: Dimitrova YN]]
		+	[[Category: Hu DX]]
		+	[[Category: Huang H]]
		+	[[Category: Lee JY]]
		+	[[Category: Lim J]]
		+	[[Category: McNamara E]]
		+	[[Category: Moffat JG]]
		+	[[Category: Murthy A]]
		+	[[Category: Pang J]]
		+	[[Category: Patel S]]
		+	[[Category: Prangley MS]]
		+	[[Category: Salphati L]]
		+	[[Category: Schutt LK]]
		+	[[Category: Siu M]]
		+	[[Category: Sneeringer CJ]]
		+	[[Category: Staben S]]
		+	[[Category: Wallweber HA]]
		+	[[Category: Wang S]]
		+	[[Category: Wang Y]]
		+	[[Category: Wu C]]
		+	[[Category: Zhao W]]

OCA at 12:48, 3 November 2021

2021-11-03T12:48:32Z

←Older revision		Revision as of 12:48, 3 November 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7rsp is ON HOLD	+	The entry 7rsp is ON HOLD until Paper Publication

	Authors:		Authors:

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

2021-08-18T05:11:42Z

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

←Older revision

Revision as of 05:11, 18 August 2021

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

2021-08-18T05:11:42Z

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

New page

'''Unreleased structure'''

The entry 7rsp is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]