6qu7 - Revision history

OCA at 07:36, 16 October 2019

OCA — Wed, 16 Oct 2019 07:36:11 GMT

←Older revision		Revision as of 07:36, 16 October 2019
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	<StructureSection load='6qu7' size='340' side='right'caption='[[6qu7]], [[Resolution\|resolution]] 1.52Å' scene=''>		<StructureSection load='6qu7' size='340' side='right'caption='[[6qu7]], [[Resolution\|resolution]] 1.52Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6qu7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QU7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QU7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6qu7]] 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=6QU7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QU7 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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=JJE:~{N}-(2-chloranyl-6-fluoranyl-phenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxidanylidene-1,2,4-triazol-1-yl]-5-fluoranyl-2-[(2~{S})-1,1,1-tris(fluoranyl)propan-2-yl]oxy-benzamide'>JJE</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"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=JJE:~{N}-(2-chloranyl-6-fluoranyl-phenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxidanylidene-1,2,4-triazol-1-yl]-5-fluoranyl-2-[(2~{S})-1,1,1-tris(fluoranyl)propan-2-yl]oxy-benzamide'>JJE</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=6qu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qu7 OCA], [http://pdbe.org/6qu7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qu7 RCSB], [http://www.ebi.ac.uk/pdbsum/6qu7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qu7 ProSAT]</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=6qu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qu7 OCA], [http://pdbe.org/6qu7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qu7 RCSB], [http://www.ebi.ac.uk/pdbsum/6qu7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qu7 ProSAT]</span></td></tr>
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	</div>		</div>
	<div class="pdbe-citations 6qu7" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6qu7" 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: Friberg, A]]		[[Category: Friberg, A]]

OCA at 22:55, 5 June 2019

OCA — Wed, 05 Jun 2019 22:55:22 GMT

←Older revision		Revision as of 22:55, 5 June 2019
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-	'''Unreleased structure'''

-	~~The entry~~ 6qu7 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of human DHODH in complex with BAY 2402234==
		+	<StructureSection load='6qu7' size='340' side='right'caption='[[6qu7]], [[Resolution\|resolution]] 1.52Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6qu7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QU7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QU7 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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=JJE:~{N}-(2-chloranyl-6-fluoranyl-phenyl)-4-[4-ethyl-3-(hydroxymethyl)-5-oxidanylidene-1,2,4-triazol-1-yl]-5-fluoranyl-2-[(2~{S})-1,1,1-tris(fluoranyl)propan-2-yl]oxy-benzamide'>JJE</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qu7 OCA], [http://pdbe.org/6qu7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qu7 RCSB], [http://www.ebi.ac.uk/pdbsum/6qu7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qu7 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 ==
		+	Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.

-	~~Authors:~~ Friberg, A.	+	The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies.,Christian S, Merz C, Evans L, Gradl S, Seidel H, Friberg A, Eheim A, Lejeune P, Brzezinka K, Zimmermann K, Ferrara S, Meyer H, Lesche R, Stoeckigt D, Bauser M, Haegebarth A, Sykes DB, Scadden DT, Losman JA, Janzer A Leukemia. 2019 Apr 2. pii: 10.1038/s41375-019-0461-5. doi:, 10.1038/s41375-019-0461-5. PMID:30940908<ref>PMID:30940908</ref>

-	~~Description: X~~-~~RAY STRUCTURE OF DHODH IN COMPLEX WITH BAY 2402234~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6qu7" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Friberg, A]]		[[Category: Friberg, A]]
		+	[[Category: Gradl, S]]
		+	[[Category: Dhodh]]
		+	[[Category: Oxidoreductase]]

OCA at 05:56, 21 May 2019

OCA — Tue, 21 May 2019 05:56:21 GMT

←Older revision		Revision as of 05:56, 21 May 2019
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6qu7 is ON HOLD	+	The entry 6qu7 is ON HOLD until Paper Publication

	Authors: Friberg, A.		Authors: Friberg, A.

OCA: Protected "6qu7" [edit=sysop:move=sysop]

OCA — Wed, 06 Mar 2019 05:55:41 GMT

Protected "6qu7" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:55, 6 March 2019

OCA: New page: '''Unreleased structure''' The entry 6qu7 is ON HOLD Authors: Friberg, A. Description: X-RAY STRUCTURE OF DHODH IN COMPLEX WITH BAY 2402234 Category: Unreleased Structures [[Catego...

OCA — Wed, 06 Mar 2019 05:55:39 GMT

New page: '''Unreleased structure''' The entry 6qu7 is ON HOLD Authors: Friberg, A. Description: X-RAY STRUCTURE OF DHODH IN COMPLEX WITH BAY 2402234 Category: Unreleased Structures [[Catego...

New page

'''Unreleased structure'''

The entry 6qu7 is ON HOLD

Authors: Friberg, A.

Description: X-RAY STRUCTURE OF DHODH IN COMPLEX WITH BAY 2402234
[[Category: Unreleased Structures]]
[[Category: Friberg, A]]