7l0k - Revision history

OCA at 15:35, 18 October 2023

OCA — Wed, 18 Oct 2023 15:35:41 GMT

←Older revision		Revision as of 15:35, 18 October 2023
Line 3:		Line 3:
	<StructureSection load='7l0k' size='340' side='right'caption='[[7l0k]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='7l0k' size='340' side='right'caption='[[7l0k]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7l0k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Plaf7 Plaf7~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L0K FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7l0k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L0K FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=XE7:3-{(1R)-1-[(3-methyl-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrrole-2-carbonyl)amino]ethyl}-1H-pyrazole-5-carboxamide'>XE7</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]] 1.96Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7l01\|7l01]]</div></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=XE7:3-{(1R)-1-[(3-methyl-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrrole-2-carbonyl)amino]ethyl}-1H-pyrazole-5-carboxamide'>XE7</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PFF0160c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [https://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=7l0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l0k OCA], [https://pdbe.org/7l0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l0k RCSB], [https://www.ebi.ac.uk/pdbsum/7l0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l0k 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=7l0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l0k OCA], [https://pdbe.org/7l0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l0k RCSB], [https://www.ebi.ac.uk/pdbsum/7l0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l0k ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.	+	[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7] 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 ==
Line 29:		Line 27:
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Plaf7~~]]	+	[[Category: Plasmodium falciparum 3D7]]
-	[[Category: Deng, X]]	+	[[Category: Deng X]]
-	[[Category: Phillips, M]]	+	[[Category: Phillips M]]
-	[[Category: Tomchick, D]]	+	[[Category: Tomchick D]]
-	~~[[Category: Alpha-beta barrel]]~~	+
-	~~[[Category: Oxidoreductase]]~~	+
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex~~]]	+

OCA at 10:05, 8 December 2021

OCA — Wed, 08 Dec 2021 10:05:47 GMT

←Older revision		Revision as of 10:05, 8 December 2021
Line 1:		Line 1:

	==Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)==		==Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)==
-	<StructureSection load='7l0k' size='340' side='right'caption='[[7l0k]]' scene=''>	+	<StructureSection load='7l0k' size='340' side='right'caption='[[7l0k]], [[Resolution\|resolution]] 1.96Å' 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=7L0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L0K FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7l0k]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plaf7 Plaf7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L0K 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=7l0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l0k OCA], [https://pdbe.org/7l0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l0k RCSB], [https://www.ebi.ac.uk/pdbsum/7l0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l0k 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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=ORO:OROTIC+ACID'>ORO</scene>, <scene name='pdbligand=XE7:3-{(1R)-1-[(3-methyl-4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1H-pyrrole-2-carbonyl)amino]ethyl}-1H-pyrazole-5-carboxamide'>XE7</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7l01\|7l01]]</div></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PFF0160c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36329 PLAF7])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydroorotate_dehydrogenase_(quinone) Dihydroorotate dehydrogenase (quinone)], with EC number [https://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=7l0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l0k OCA], [https://pdbe.org/7l0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l0k RCSB], [https://www.ebi.ac.uk/pdbsum/7l0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l0k ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/PYRD_PLAF7 PYRD_PLAF7]] Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.
		+
		+	Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.,Palmer MJ, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White KL, Striepen J, Bath J, Schindler KA, Yeo T, Shackleford DM, Mok S, Deni I, Lawong A, Huang A, Chen G, Wang W, Jayaseelan J, Katneni K, Patil R, Saunders J, Shahi SP, Chittimalla R, Angulo-Barturen I, Jimenez-Diaz MB, Wittlin S, Tumwebaze PK, Rosenthal PJ, Cooper RA, Aguiar ACC, Guido RVC, Pereira DB, Mittal N, Winzeler EA, Tomchick DR, Laleu B, Burrows JN, Rathod PK, Fidock DA, Charman SA, Phillips MA J Med Chem. 2021 May 13;64(9):6085-6136. doi: 10.1021/acs.jmedchem.1c00173. Epub , 2021 Apr 20. PMID:33876936<ref>PMID:33876936</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7l0k" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dihydroorotate dehydrogenase 3D structures\|Dihydroorotate dehydrogenase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Deng X]]	+	[[Category: Plaf7]]
-	[[Category: Phillips M]]	+	[[Category: Deng, X]]
-	[[Category: Tomchick D]]	+	[[Category: Phillips, M]]
		+	[[Category: Tomchick, D]]
		+	[[Category: Alpha-beta barrel]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]

OCA at 10:10, 19 May 2021

OCA — Wed, 19 May 2021 10:10:22 GMT

←Older revision		Revision as of 10:10, 19 May 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 7l0k is ON HOLD~~	+	==Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)==
-		+	<StructureSection load='7l0k' size='340' side='right'caption='[[7l0k]]' scene=''>
-	~~Authors: Deng, X., Phillips, M., Tomchick, D.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L0K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L0K FirstGlance]. <br>
-	~~Description:~~ Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)	+	</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=7l0k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l0k OCA], [https://pdbe.org/7l0k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l0k RCSB], [https://www.ebi.ac.uk/pdbsum/7l0k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l0k ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Tomchick~~, D]]	+	__TOC__
-	[[Category: Deng, X]]	+	</StructureSection>
-	[[Category: Phillips, M]]	+	[[Category: Large Structures]]
		+	[[Category: Deng X]]
		+	[[Category: Phillips M]]
		+	[[Category: Tomchick D]]

OCA: Protected "7l0k" [edit=sysop:move=sysop]

OCA — Thu, 24 Dec 2020 08:05:04 GMT

Protected "7l0k" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:05, 24 December 2020

OCA: New page: '''Unreleased structure''' The entry 7l0k is ON HOLD Authors: Deng, X., Phillips, M., Tomchick, D. Description: Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase ...

OCA — Thu, 24 Dec 2020 08:05:02 GMT

New page: '''Unreleased structure''' The entry 7l0k is ON HOLD Authors: Deng, X., Phillips, M., Tomchick, D. Description: Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase ...

New page

'''Unreleased structure'''

The entry 7l0k is ON HOLD

Authors: Deng, X., Phillips, M., Tomchick, D.

Description: Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM784 (3-(1-(3-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrrole-2-carboxamido)ethyl)-1H-pyrazole-5-carboxamide)
[[Category: Unreleased Structures]]
[[Category: Tomchick, D]]
[[Category: Deng, X]]
[[Category: Phillips, M]]