6et4 - Revision history

OCA at 09:14, 11 November 2020

OCA — Wed, 11 Nov 2020 09:14:57 GMT

←Older revision		Revision as of 09:14, 11 November 2020
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	==HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR==		==HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR==
-	<StructureSection load='6et4' size='340' side='right' caption='[[6et4]], [[Resolution\|resolution]] 1.70Å' scene=''>	+	<StructureSection load='6et4' size='340' side='right'caption='[[6et4]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6et4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ET4 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6ET4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6et4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ET4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ET4 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DDQ:DECYLAMINE-N,N-DIMETHYL-N-OXIDE'>DDQ</scene>, <scene name='pdbligand=DOR:(4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC+ACID'>DOR</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SDV:N-[(4R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2,1-benzoxazole-3-carboxamide'>SDV</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=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DDQ:DECYLAMINE-N,N-DIMETHYL-N-OXIDE'>DDQ</scene>, <scene name='pdbligand=DOR:(4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC+ACID'>DOR</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SDV:N-[(4R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2,1-benzoxazole-3-carboxamide'>SDV</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='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=6et4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6et4 OCA], [http://pdbe.org/6et4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6et4 RCSB], [http://www.ebi.ac.uk/pdbsum/6et4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6et4 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=6et4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6et4 OCA], [http://pdbe.org/6et4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6et4 RCSB], [http://www.ebi.ac.uk/pdbsum/6et4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6et4 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
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	</div>		</div>
	<div class="pdbe-citations 6et4" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6et4" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Dihydroorotate dehydrogenase 3D structures\|Dihydroorotate dehydrogenase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Gustavsson, A L]]		[[Category: Gustavsson, A L]]
	[[Category: Hakansson, M]]		[[Category: Hakansson, M]]

OCA at 06:41, 28 March 2018

OCA — Wed, 28 Mar 2018 06:41:35 GMT

←Older revision		Revision as of 06:41, 28 March 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6et4 is ~~ON HOLD~~	+	==HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR==
		+	<StructureSection load='6et4' size='340' side='right' caption='[[6et4]], [[Resolution\|resolution]] 1.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6et4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ET4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ET4 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DDQ:DECYLAMINE-N,N-DIMETHYL-N-OXIDE'>DDQ</scene>, <scene name='pdbligand=DOR:(4S)-2,6-DIOXOHEXAHYDROPYRIMIDINE-4-CARBOXYLIC+ACID'>DOR</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SDV:N-[(4R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydroindazol-4-yl]-2,1-benzoxazole-3-carboxamide'>SDV</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6et4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6et4 OCA], [http://pdbe.org/6et4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6et4 RCSB], [http://www.ebi.ac.uk/pdbsum/6et4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6et4 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 ==
		+	The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

-	~~Authors: Hakansson~~, M., ~~Walse~~, B., Gustavsson, A.-L., ~~Lain~~, S.	+	A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.,Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, Pastor Fernandez A, Mollick T, Darekar S, Sedimbi SK, Nekulova M, Sachweh MCC, Campbell J, Higgins M, Tuck C, Popa M, Safont MM, Gelebart P, Fandalyuk Z, Thompson AM, Svensson R, Gustavsson AL, Johansson L, Farnegardh K, Yngve U, Saleh A, Haraldsson M, D'Hollander ACA, Franco M, Zhao Y, Hakansson M, Walse B, Larsson K, Peat EM, Pelechano V, Lunec J, Vojtesek B, Carmena M, Earnshaw WC, McCarthy AR, Westwood NJ, Arsenian-Henriksson M, Lane DP, Bhatia R, McCormack E, Lain S Nat Commun. 2018 Mar 16;9(1):1107. doi: 10.1038/s41467-018-03441-3. PMID:29549331<ref>PMID:29549331</ref>

-	~~Description: HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Lain, S]]~~	+	<div class="pdbe-citations 6et4" style="background-color:#fffaf0;"></div>
-	[[Category: Gustavsson, A.-L]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Gustavsson, A L]]
	[[Category: Hakansson, M]]		[[Category: Hakansson, M]]
		+	[[Category: Lain, S]]
	[[Category: Walse, B]]		[[Category: Walse, B]]
		+	[[Category: Cancer]]
		+	[[Category: Dhodh]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: P53 activation]]
		+	[[Category: Pyrimidine synthesis]]

OCA: Protected "6et4" [edit=sysop:move=sysop]

OCA — Wed, 01 Nov 2017 05:06:27 GMT

Protected "6et4" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:06, 1 November 2017

OCA: New page: '''Unreleased structure''' The entry 6et4 is ON HOLD Authors: Hakansson, M., Walse, B., Gustavsson, A.-L., Lain, S. Description: HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVE...

OCA — Wed, 01 Nov 2017 05:06:26 GMT

New page: '''Unreleased structure''' The entry 6et4 is ON HOLD Authors: Hakansson, M., Walse, B., Gustavsson, A.-L., Lain, S. Description: HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVE...

New page

'''Unreleased structure'''

The entry 6et4 is ON HOLD

Authors: Hakansson, M., Walse, B., Gustavsson, A.-L., Lain, S.

Description: HUMAN DIHYDROOROTATE DEHYDROGENASE IN COMPLEX WITH NOVEL INHIBITOR
[[Category: Unreleased Structures]]
[[Category: Lain, S]]
[[Category: Gustavsson, A.-L]]
[[Category: Hakansson, M]]
[[Category: Walse, B]]