4ja8

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==Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor==
==Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor==
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<StructureSection load='4ja8' size='340' side='right' caption='[[4ja8]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
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<StructureSection load='4ja8' size='340' side='right'caption='[[4ja8]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4ja8]] 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=4JA8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JA8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4ja8]] 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=4JA8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JA8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1K9:1-[5-(CYCLOPROPYLSULFAMOYL)-2-THIOPHEN-3-YL-PHENYL]-3-[3-(TRIFLUOROMETHYL)PHENYL]UREA'>1K9</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1K9:1-[5-(CYCLOPROPYLSULFAMOYL)-2-THIOPHEN-3-YL-PHENYL]-3-[3-(TRIFLUOROMETHYL)PHENYL]UREA'>1K9</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr>
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<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>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ja8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ja8 OCA], [https://pdbe.org/4ja8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ja8 RCSB], [https://www.ebi.ac.uk/pdbsum/4ja8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ja8 ProSAT]</span></td></tr>
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<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=4ja8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ja8 OCA], [http://pdbe.org/4ja8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ja8 RCSB], [http://www.ebi.ac.uk/pdbsum/4ja8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ja8 ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN]] D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:[http://omim.org/entry/613657 613657]]. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.<ref>PMID:20847235</ref>
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[https://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN] D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM:[https://omim.org/entry/613657 613657]. D2HGA2 is a neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. Both a mild and a severe phenotype exist. The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and cardiomyopathy. The mild phenotype has a more variable clinical presentation. Diagnosis is based on the presence of an excess of D-2-hydroxyglutaric acid in the urine.<ref>PMID:20847235</ref>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN]] Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
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[https://www.uniprot.org/uniprot/IDHP_HUMAN IDHP_HUMAN] Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases- 1 and -2 (IDH1, IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite R (-)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia (AML) cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
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Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation.,Wang F, Travins J, Delabarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE Science. 2013 Apr 4. PMID:23558173<ref>PMID:23558173</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4ja8" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Isocitrate dehydrogenase|Isocitrate dehydrogenase]]
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*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Chen, L]]
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[[Category: Large Structures]]
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[[Category: DeLaBarre, B]]
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[[Category: Chen L]]
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[[Category: Jiang, F]]
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[[Category: DeLaBarre B]]
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[[Category: Qian, K]]
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[[Category: Jiang F]]
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[[Category: Travins, J]]
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[[Category: Qian K]]
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[[Category: Wei, W]]
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[[Category: Travins J]]
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[[Category: Wu, M]]
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[[Category: Wei W]]
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[[Category: Metabolic enzyme oncometabolite]]
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[[Category: Wu M]]
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[[Category: Oxidoreductase-oxidoreductase inhibitor complex]]
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[[Category: Protein-inhibitor complex]]
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Current revision

Complex of Mitochondrial Isocitrate Dehydrogenase R140Q Mutant with AGI-6780 Inhibitor

PDB ID 4ja8

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