OCA at 11:03, 22 November 2023

2023-11-22T11:03:38Z

←Older revision		Revision as of 11:03, 22 November 2023
Line 1:		Line 1:

	==Discovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma==		==Discovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma==
-	<StructureSection load='6llx' size='340' side='right'caption='[[6llx]]' scene=''>	+	<StructureSection load='6llx' size='340' side='right'caption='[[6llx]], [[Resolution\|resolution]] 1.58Å' 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=6LLX OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6LLX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6llx]] 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=6LLX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LLX FirstGlance]. <br>
-	</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=6llx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6llx OCA], [~~http~~://pdbe.org/6llx PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6llx RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6llx PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6llx ProSAT]</span></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]] 1.581Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GSH:GLUTATHIONE'>GSH</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</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=6llx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6llx OCA], [https://pdbe.org/6llx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6llx RCSB], [https://www.ebi.ac.uk/pdbsum/6llx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6llx ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/GSTP1_HUMAN GSTP1_HUMAN] Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.<ref>PMID:21668448</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	BACKGROUND: Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. METHODS: High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. RESULTS: We identified a small molecular inhibitor, "MNPC," that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. CONCLUSIONS: Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.
		+
		+	Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.,Lei K, Gu X, Alvarado AG, Du Y, Luo S, Ahn EH, Kang SS, Ji B, Liu X, Mao H, Fu H, Kornblum HI, Jin L, Li H, Ye K J Hematol Oncol. 2020 Oct 21;13(1):141. doi: 10.1186/s13045-020-00979-y. PMID:33087132<ref>PMID:33087132</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6llx" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Glutathione S-transferase 3D structures\|Glutathione S-transferase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Lei KC]]		[[Category: Lei KC]]
	[[Category: Li H]]		[[Category: Li H]]
	[[Category: Ye K]]		[[Category: Ye K]]

OCA at 06:51, 25 November 2020

2020-11-25T06:51:54Z

←Older revision		Revision as of 06:51, 25 November 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6llx is ~~ON HOLD until Paper Publication~~	+	==Discovery of A Dual Inhibitor of NQO1 and GSTP1 for Treating Malignant Glioblastoma==
-		+	<StructureSection load='6llx' size='340' side='right'caption='[[6llx]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LLX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6LLX FirstGlance]. <br>
-	~~Description~~:	+	</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=6llx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6llx OCA], [http://pdbe.org/6llx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6llx RCSB], [http://www.ebi.ac.uk/pdbsum/6llx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6llx ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Lei KC]]
		+	[[Category: Li H]]
		+	[[Category: Ye K]]

OCA at 12:58, 29 January 2020

2020-01-29T12:58:53Z

←Older revision		Revision as of 12:58, 29 January 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors:		Authors:

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

2020-01-01T06:38:18Z

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

←Older revision

Revision as of 06:38, 1 January 2020

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

2020-01-01T06:38:16Z

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

New page

'''Unreleased structure'''

The entry 6llx is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]

6llx - Revision history

OCA at 11:03, 22 November 2023

OCA at 06:51, 25 November 2020

OCA at 12:58, 29 January 2020

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

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