6jme - Revision history

OCA at 10:38, 27 March 2024

OCA — Wed, 27 Mar 2024 10:38:38 GMT

←Older revision		Revision as of 10:38, 27 March 2024
Line 3:		Line 3:
	<StructureSection load='6jme' size='340' side='right'caption='[[6jme]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='6jme' size='340' side='right'caption='[[6jme]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6jme]] is a 1 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=6JME OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6JME FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jme]] is a 1 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=6JME OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JME FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BVU:3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione'>BVU</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.8Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHODH ([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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BVU:3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione'>BVU</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=6jme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jme OCA], [https://pdbe.org/6jme PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jme RCSB], [https://www.ebi.ac.uk/pdbsum/6jme PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jme ProSAT]</span></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=6jme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jme OCA], [~~http~~://pdbe.org/6jme PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6jme RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6jme PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6jme ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[~~http~~://omim.org/entry/263750 263750]]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref>	+	[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[https://omim.org/entry/263750 263750]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.	+	[https://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.	+
-		+
-	Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.,Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y J Med Chem. 2020 Jul 23;63(14):7633-7652. doi: 10.1021/acs.jmedchem.0c00512. Epub, 2020 Jul 1. PMID:32496056<ref>PMID:32496056</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6jme" style="background-color:#fffaf0;"></div>~~	+

	==See Also==		==See Also==
Line 29:		Line 19:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chen, Q]]	+	[[Category: Chen Q]]
-	[[Category: Yu, Y]]	+	[[Category: Yu Y]]
-	~~[[Category: Complex]]~~	+
-	~~[[Category: Dhodh]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]	+

OCA at 07:19, 30 September 2020

OCA — Wed, 30 Sep 2020 07:19:16 GMT

←Older revision		Revision as of 07:19, 30 September 2020
Line 3:		Line 3:
	<StructureSection load='6jme' size='340' side='right'caption='[[6jme]], [[Resolution\|resolution]] 1.80Å' scene=''>		<StructureSection load='6jme' size='340' side='right'caption='[[6jme]], [[Resolution\|resolution]] 1.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6jme]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JME OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6JME FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6jme]] is a 1 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=6JME OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6JME FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BVU:3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione'>BVU</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BVU:3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione'>BVU</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">DHODH ([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/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=6jme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jme OCA], [http://pdbe.org/6jme PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jme RCSB], [http://www.ebi.ac.uk/pdbsum/6jme PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jme ProSAT]</span></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=6jme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jme OCA], [http://pdbe.org/6jme PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jme RCSB], [http://www.ebi.ac.uk/pdbsum/6jme PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jme ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 12:		Line 13:
	== Function ==		== Function ==
	[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.		[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
		+
		+	Bifunctional Naphtho[2,3-d][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.,Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y J Med Chem. 2020 Jul 23;63(14):7633-7652. doi: 10.1021/acs.jmedchem.0c00512. Epub, 2020 Jul 1. PMID:32496056<ref>PMID:32496056</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6jme" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dihydroorotate dehydrogenase 3D structures\|Dihydroorotate dehydrogenase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Chen, Q]]		[[Category: Chen, Q]]

OCA at 09:37, 18 March 2020

OCA — Wed, 18 Mar 2020 09:37:59 GMT

←Older revision		Revision as of 09:37, 18 March 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6jme is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of human DHODH in complex with inhibitor 0946==
-		+	<StructureSection load='6jme' size='340' side='right'caption='[[6jme]], [[Resolution\|resolution]] 1.80Å' scene=''>
-	~~Authors~~: Yu, Y., ~~Chen~~, Q.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[6jme]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JME OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JME FirstGlance]. <br>
-	~~Description~~: ~~Crystal structure of human DHODH~~ in ~~complex~~ with ~~inhibitor 0946~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BVU:3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione'>BVU</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=LDA:LAURYL+DIMETHYLAMINE-N-OXIDE'>LDA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.5.2 1.3.5.2] </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=6jme FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jme OCA], [http://pdbe.org/6jme PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jme RCSB], [http://www.ebi.ac.uk/pdbsum/6jme PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jme ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Defects in DHODH are the cause of postaxial acrofacial dysostosis (POADS) [MIM:[http://omim.org/entry/263750 263750]]; also known as Miller syndrome. POADS is characterized by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the posterior elements of the limbs, coloboma of the eyelids and supernumerary nipples. POADS is a very rare disorder: only 2 multiplex families, each consisting of 2 affected siblings born to unaffected, nonconsanguineous parents, have been described among a total of around 30 reported cases.<ref>PMID:19915526</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PYRD_HUMAN PYRD_HUMAN]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Chen, Q]]
	[[Category: Yu, Y]]		[[Category: Yu, Y]]
-	[[Category: ~~Chen, Q~~]]	+	[[Category: Complex]]
		+	[[Category: Dhodh]]
		+	[[Category: Inhibitor]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 04:56, 6 November 2019

OCA — Wed, 06 Nov 2019 04:56:12 GMT

←Older revision		Revision as of 04:56, 6 November 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

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

	Authors: Yu, Y., Chen, Q.		Authors: Yu, Y., Chen, Q.

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

OCA — Wed, 13 Mar 2019 10:06:24 GMT

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

←Older revision

Revision as of 10:06, 13 March 2019

OCA: New page: '''Unreleased structure''' The entry 6jme is ON HOLD Authors: Yu, Y., Chen, Q. Description: Crystal structure of human DHODH in complex with inhibitor 0946 [[Category: Unreleased Struc...

OCA — Wed, 13 Mar 2019 10:06:22 GMT

New page: '''Unreleased structure''' The entry 6jme is ON HOLD Authors: Yu, Y., Chen, Q. Description: Crystal structure of human DHODH in complex with inhibitor 0946 [[Category: Unreleased Struc...

New page

'''Unreleased structure'''

The entry 6jme is ON HOLD

Authors: Yu, Y., Chen, Q.

Description: Crystal structure of human DHODH in complex with inhibitor 0946
[[Category: Unreleased Structures]]
[[Category: Yu, Y]]
[[Category: Chen, Q]]