4xs3 - Revision history

OCA at 13:01, 1 March 2024

OCA — Fri, 01 Mar 2024 13:01:34 GMT

←Older revision		Revision as of 13:01, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4xs3]] is a 2 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=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4xs3]] is a 2 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=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</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]] 3.291Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [https://pdbe.org/4xs3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [https://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [https://pdbe.org/4xs3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [https://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 ProSAT]</span></td></tr>
	</table>		</table>
Line 11:		Line 12:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]		[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.
-
-	Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.,Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y J Med Chem. 2015 Sep 10;58(17):6899-908. doi: 10.1021/acs.jmedchem.5b00684. Epub , 2015 Aug 26. PMID:26280302<ref>PMID:26280302</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4xs3" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Isocitrate dehydrogenase 3D structures\|Isocitrate dehydrogenase 3D structures]]		*[[Isocitrate dehydrogenase 3D structures\|Isocitrate dehydrogenase 3D structures]]
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 17:49, 26 April 2023

OCA — Wed, 26 Apr 2023 17:49:39 GMT

←Older revision		Revision as of 17:49, 26 April 2023
Line 3:		Line 3:
	<StructureSection load='4xs3' size='340' side='right'caption='[[4xs3]], [[Resolution\|resolution]] 3.29Å' scene=''>		<StructureSection load='4xs3' size='340' side='right'caption='[[4xs3]], [[Resolution\|resolution]] 3.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4xs3]] is a 2 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=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4xs3]] is a 2 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=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4xrx\|4xrx]]</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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [https://pdbe.org/4xs3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [https://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 ProSAT]</span></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">IDH1, PICD ([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/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [~~http~~://pdbe.org/4xs3 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[~~http~~://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.	+	[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[https://omim.org/entry/137800 137800]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Jiang, H]]	+	[[Category: Jiang H]]
-	[[Category: Kogiso, M]]	+	[[Category: Kogiso M]]
-	[[Category: Li, X]]	+	[[Category: Li X]]
-	[[Category: Song, Y]]	+	[[Category: Song Y]]
-	[[Category: Wu, F]]	+	[[Category: Wu F]]
-	[[Category: Yao, Y]]	+	[[Category: Yao Y]]
-	[[Category: Zheng, B]]	+	[[Category: Zheng B]]
-	[[Category: Zhou, C]]	+	[[Category: Zhou C]]
-	~~[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]~~	+
-	~~[[Category: Oxidoreductase/oxidoreductase inhibitor~~]]	+

OCA at 08:43, 18 December 2019

OCA — Wed, 18 Dec 2019 08:43:05 GMT

←Older revision		Revision as of 08:43, 18 December 2019
Line 23:		Line 23:

	==See Also==		==See Also==
-	*[[Isocitrate dehydrogenase\|Isocitrate dehydrogenase]]	+	*[[Isocitrate dehydrogenase 3D structures\|Isocitrate dehydrogenase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 07:30, 24 April 2019

OCA — Wed, 24 Apr 2019 07:30:26 GMT

←Older revision		Revision as of 07:30, 24 April 2019
Line 1:		Line 1:

	==Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one==		==Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one==
-	<StructureSection load='4xs3' size='340' side='right' caption='[[4xs3]], [[Resolution\|resolution]] 3.29Å' scene=''>	+	<StructureSection load='4xs3' size='340' side='right'caption='[[4xs3]], [[Resolution\|resolution]] 3.29Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4xs3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4xs3]] is a 2 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=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4xrx\|4xrx]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4xrx\|4xrx]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">IDH1, PICD ([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/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [http://pdbe.org/4xs3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [http://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [http://pdbe.org/4xs3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [http://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 ProSAT]</span></td></tr>
Line 27:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Jiang, H]]		[[Category: Jiang, H]]
	[[Category: Kogiso, M]]		[[Category: Kogiso, M]]

OCA at 10:49, 13 September 2017

OCA — Wed, 13 Sep 2017 10:49:44 GMT

←Older revision		Revision as of 10:49, 13 September 2017
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 4xs3" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4xs3" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Isocitrate dehydrogenase\|Isocitrate dehydrogenase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 15:32, 27 July 2016

OCA — Wed, 27 Jul 2016 15:32:19 GMT

←Older revision		Revision as of 15:32, 27 July 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 4xs3 is ~~ON HOLD~~	+	==Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one==
		+	<StructureSection load='4xs3' size='340' side='right' caption='[[4xs3]], [[Resolution\|resolution]] 3.29Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4xs3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XS3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XS3 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=42W:(E)-1-BENZYL-5-((1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL)PYRIDIN-2(1H)-ONE'>42W</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4xrx\|4xrx]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Isocitrate_dehydrogenase_(NADP(+)) Isocitrate dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.42 1.1.1.42] </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=4xs3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xs3 OCA], [http://pdbe.org/4xs3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xs3 RCSB], [http://www.ebi.ac.uk/pdbsum/4xs3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xs3 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN]] Defects in IDH1 are involved in the development of glioma (GLM) [MIM:[http://omim.org/entry/137800 137800]]. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Mutations affecting Arg-132 are tissue-specific, and suggest that this residue plays a unique role in the development of high-grade gliomas. Mutations of Arg-132 to Cys, His, Leu or Ser abolish magnesium binding and abolish the conversion of isocitrate to alpha-ketoglutarate. Instead, alpha-ketoglutarate is converted to R(-)-2-hydroxyglutarate. Elevated levels of R(-)-2-hydroxyglutarate are correlated with an elevated risk of malignant brain tumors.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation.

-	~~Authors: Zheng, B~~., Wu, F., Jiang, H., ~~Kogiso~~, M., Yao, Y., Zhou, C., Li~~, X.~~, Song, Y.	+	Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.,Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y J Med Chem. 2015 Sep 10;58(17):6899-908. doi: 10.1021/acs.jmedchem.5b00684. Epub , 2015 Aug 26. PMID:26280302<ref>PMID:26280302</ref>

-	~~Description: Crystal structure~~ of ~~a metabolic reductase with (E)~~-1-~~benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	[[Category: Li, X]]	+	<div class="pdbe-citations 4xs3" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Jiang, H]]
	[[Category: Kogiso, M]]		[[Category: Kogiso, M]]
		+	[[Category: Li, X]]
	[[Category: Song, Y]]		[[Category: Song, Y]]
-	[[Category: Zheng, B]]
-	[[Category: Yao, Y]]
-	[[Category: Jiang, H]]
	[[Category: Wu, F]]		[[Category: Wu, F]]
		+	[[Category: Yao, Y]]
		+	[[Category: Zheng, B]]
	[[Category: Zhou, C]]		[[Category: Zhou, C]]
		+	[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
		+	[[Category: Oxidoreductase/oxidoreductase inhibitor]]

OCA at 23:18, 30 November 2015

OCA — Mon, 30 Nov 2015 23:18:20 GMT

←Older revision		Revision as of 23:18, 30 November 2015
Line 7:		Line 7:
	Description: Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one		Description: Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
		+	[[Category: Li, X]]
	[[Category: Kogiso, M]]		[[Category: Kogiso, M]]
	[[Category: Song, Y]]		[[Category: Song, Y]]
-	[[Category: Li, X]]
	[[Category: Zheng, B]]		[[Category: Zheng, B]]
	[[Category: Yao, Y]]		[[Category: Yao, Y]]

OCA at 14:45, 7 February 2015

OCA — Sat, 07 Feb 2015 14:45:51 GMT

←Older revision		Revision as of 14:45, 7 February 2015
Line 3:		Line 3:
	The entry 4xs3 is ON HOLD		The entry 4xs3 is ON HOLD

-	Authors: Wu, F., ~~Zheng~~, B., Jiang, H., Kogiso, M., Yao, Y., Zhou, C., Li, X., Song, Y.	+	Authors: Zheng, B., Wu, F., Jiang, H., Kogiso, M., Yao, Y., Zhou, C., Li, X., Song, Y.

	Description: Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one		Description: Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one

OCA: Protected "4xs3" [edit=sysop:move=sysop]

OCA — Wed, 28 Jan 2015 15:46:30 GMT

Protected "4xs3" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:46, 28 January 2015

OCA: New page: '''Unreleased structure''' The entry 4xs3 is ON HOLD Authors: Wu, F., Zheng, B., Jiang, H., Kogiso, M., Yao, Y., Zhou, C., Li, X., Song, Y. Description: Crystal structure of a metaboli...

OCA — Wed, 28 Jan 2015 15:46:28 GMT

New page: '''Unreleased structure''' The entry 4xs3 is ON HOLD Authors: Wu, F., Zheng, B., Jiang, H., Kogiso, M., Yao, Y., Zhou, C., Li, X., Song, Y. Description: Crystal structure of a metaboli...

New page

'''Unreleased structure'''

The entry 4xs3 is ON HOLD

Authors: Wu, F., Zheng, B., Jiang, H., Kogiso, M., Yao, Y., Zhou, C., Li, X., Song, Y.

Description: Crystal structure of a metabolic reductase with (E)-1-benzyl-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one
[[Category: Unreleased Structures]]
[[Category: Kogiso, M]]
[[Category: Song, Y]]
[[Category: Li, X]]
[[Category: Zheng, B]]
[[Category: Yao, Y]]
[[Category: Jiang, H]]
[[Category: Wu, F]]
[[Category: Zhou, C]]