5mut - Revision history

OCA at 17:50, 8 November 2023

2023-11-08T17:50:44Z

← Older revision		Revision as of 17:50, 8 November 2023
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	<StructureSection load='5mut' size='340' side='right'caption='[[5mut]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='5mut' size='340' side='right'caption='[[5mut]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5mut]] 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=5MUT OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5MUT FirstGlance]. <br>		<table><tr><td colspan='2'>[[5mut]] 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=5MUT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5MUT 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=HYT:2-METHYL-5-OXIDANYL-~{N}-[2,3,5,6-TETRAKIS(FLUORANYL)-4-PHENYL-PHENYL]-1,2,3-TRIAZOLE-4-CARBOXAMIDE'>HYT</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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]] 1.75Å</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=HYT:2-METHYL-5-OXIDANYL-~{N}-[2,3,5,6-TETRAKIS(FLUORANYL)-4-PHENYL-PHENYL]-1,2,3-TRIAZOLE-4-CARBOXAMIDE'>HYT</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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=5mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mut OCA], [https://pdbe.org/5mut PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5mut RCSB], [https://www.ebi.ac.uk/pdbsum/5mut PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5mut 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=5mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mut OCA], [~~http~~://pdbe.org/5mut PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5mut RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5mut PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5mut 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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Al-Kadaraghi, S]]		[[Category: Al-Kadaraghi S]]
	[[Category: Andersson, M]]		[[Category: Andersson M]]
	[[Category: Boschi, D]]		[[Category: Boschi D]]
	[[Category: Friemann, R]]		[[Category: Friemann R]]
	[[Category: Goyal, P]]		[[Category: Goyal P]]
	[[Category: Lolli, M]]		[[Category: Lolli M]]
	[[Category: Moritzer~~, A C~~]]		[[Category: Moritzer AC]]
	[[Category: Pippione~~, A C~~]]		[[Category: Pippione AC]]
	[[Category: Sainas, S]]		[[Category: Sainas S]]
	~~[[Category: Dhodh]]~~
	~~[[Category: Human dhodh]]~~
	~~[[Category: Oxidoreductase~~]]

OCA at 07:29, 19 August 2020

2020-08-19T07:29:40Z

← Older revision		Revision as of 07:29, 19 August 2020
Line 1:		Line 1:

	==Crystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds==		==Crystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds==
	<StructureSection load='5mut' size='340' side='right' caption='[[5mut]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='5mut' size='340' side='right'caption='[[5mut]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[5mut]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MUT OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca.weizmann.ac~~.~~il/oca-docs~~/fgij/fg.htm?mol=5MUT FirstGlance]. <br>		<table><tr><td colspan='2'>[[5mut]] 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=5MUT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5MUT 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=HYT:2-METHYL-5-OXIDANYL-~{N}-[2,3,5,6-TETRAKIS(FLUORANYL)-4-PHENYL-PHENYL]-1,2,3-TRIAZOLE-4-CARBOXAMIDE'>HYT</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=HYT:2-METHYL-5-OXIDANYL-~{N}-[2,3,5,6-TETRAKIS(FLUORANYL)-4-PHENYL-PHENYL]-1,2,3-TRIAZOLE-4-CARBOXAMIDE'>HYT</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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=5mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mut OCA], [http://pdbe.org/5mut PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mut RCSB], [http://www.ebi.ac.uk/pdbsum/5mut PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mut 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=5mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mut OCA], [http://pdbe.org/5mut PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mut RCSB], [http://www.ebi.ac.uk/pdbsum/5mut PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mut ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 21:		Line 22:
	</div>		</div>
	<div class="pdbe-citations 5mut" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5mut" 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: Al-Kadaraghi, S]]		[[Category: Al-Kadaraghi, S]]
	[[Category: Andersson, M]]		[[Category: Andersson, M]]

OCA at 16:47, 9 March 2017

2017-03-09T16:47:20Z

← Older revision		Revision as of 16:47, 9 March 2017
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The~~ entry ~~5mut~~ is ~~ON HOLD~~		==Crystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds==
			<StructureSection load='5mut' size='340' side='right' caption='[[5mut]], [[Resolution\|resolution]] 1.75Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[5mut]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5MUT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5MUT 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=HYT:2-METHYL-5-OXIDANYL-~{N}-[2,3,5,6-TETRAKIS(FLUORANYL)-4-PHENYL-PHENYL]-1,2,3-TRIAZOLE-4-CARBOXAMIDE'>HYT</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5mut FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5mut OCA], [http://pdbe.org/5mut PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5mut RCSB], [http://www.ebi.ac.uk/pdbsum/5mut PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5mut 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.
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.

	~~Authors: Goyal~~, P., ~~Andersson~~, M., ~~Moritzer~~, A.C., ~~Sainas~~, S., ~~Pippione~~, ~~A.C.~~, ~~Boschi~~, D., Al-Kadaraghi, S.		Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.,Sainas S, Pippione AC, Giorgis M, Lupino E, Goyal P, Ramondetti C, Buccinna B, Piccinini M, Braga RC, Andrade CH, Andersson M, Moritzer AC, Friemann R, Mensa S, Al-Kadaraghi S, Boschi D, Lolli ML Eur J Med Chem. 2017 Mar 31;129:287-302. doi: 10.1016/j.ejmech.2017.02.017. Epub , 2017 Feb 14. PMID:28235702<ref>PMID:28235702</ref>

	~~Description: Crystal structure~~ of ~~potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[Category~~: ~~Unreleased Structures]]~~		</div>
	~~[[Category: Sainas, S]]~~		<div class="pdbe-citations 5mut" style="background-color:#fffaf0;"></div>
	~~[[Category: Goyal, P]]~~		== References ==
	[[Category: ~~Pippione~~, ~~A.C~~]]		<references/>
			__TOC__
			</StructureSection>
			[[Category: Al-Kadaraghi, S]]
	[[Category: Andersson, M]]		[[Category: Andersson, M]]
	~~[[Category: Al-Kadaraghi, S]]~~
	[[Category: Boschi, D]]		[[Category: Boschi, D]]
	[[Category: Moritzer, A.C]]		[[Category: Friemann, R]]
			[[Category: Goyal, P]]
			[[Category: Lolli, M]]
			[[Category: Moritzer, A C]]
			[[Category: Pippione, A C]]
			[[Category: Sainas, S]]
			[[Category: Dhodh]]
			[[Category: Human dhodh]]
			[[Category: Oxidoreductase]]

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

2017-01-25T20:35:53Z

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

← Older revision	Revision as of 20:35, 25 January 2017
(No difference)

OCA: New page: '''Unreleased structure''' The entry 5mut is ON HOLD Authors: Goyal, P., Andersson, M., Moritzer, A.C., Sainas, S., Pippione, A.C., Boschi, D., Al-Kadaraghi, S. Description: Crystal st...

2017-01-25T20:35:52Z

New page: '''Unreleased structure''' The entry 5mut is ON HOLD Authors: Goyal, P., Andersson, M., Moritzer, A.C., Sainas, S., Pippione, A.C., Boschi, D., Al-Kadaraghi, S. Description: Crystal st...

New page

'''Unreleased structure'''

The entry 5mut is ON HOLD

Authors: Goyal, P., Andersson, M., Moritzer, A.C., Sainas, S., Pippione, A.C., Boschi, D., Al-Kadaraghi, S.

Description: Crystal structure of potent human Dihydroorotate Dehydrogenase inhibitors based on hydroxylated azole scaffolds
[[Category: Unreleased Structures]]
[[Category: Sainas, S]]
[[Category: Goyal, P]]
[[Category: Pippione, A.C]]
[[Category: Andersson, M]]
[[Category: Al-Kadaraghi, S]]
[[Category: Boschi, D]]
[[Category: Moritzer, A.C]]