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| | <StructureSection load='5svn' size='340' side='right'caption='[[5svn]], [[Resolution|resolution]] 2.10Å' scene=''> | | <StructureSection load='5svn' size='340' side='right'caption='[[5svn]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5svn]] 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=5SVN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5SVN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5svn]] 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=5SVN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5SVN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.1Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5sun|5sun]], [[5svo|5svo]], [[5svf|5svf]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> |
| - | <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> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5svn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5svn OCA], [https://pdbe.org/5svn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5svn RCSB], [https://www.ebi.ac.uk/pdbsum/5svn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5svn ProSAT]</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://proteopedia.org/fgij/fg.htm?mol=5svn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5svn OCA], [http://pdbe.org/5svn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5svn RCSB], [http://www.ebi.ac.uk/pdbsum/5svn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5svn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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> | + | [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 == |
| - | [[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. | + | [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. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.
| + | |
| - | | + | |
| - | Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity.,Xie X, Baird D, Bowen K, Capka V, Chen J, Chenail G, Cho Y, Dooley J, Farsidjani A, Fortin P, Kohls D, Kulathila R, Lin F, McKay D, Rodrigues L, Sage D, Toure BB, van der Plas S, Wright K, Xu M, Yin H, Levell J, Pagliarini RA Structure. 2017 Mar 7;25(3):506-513. doi: 10.1016/j.str.2016.12.017. Epub 2017, Jan 26. PMID:28132785<ref>PMID:28132785</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5svn" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Kulathila, R]] | + | [[Category: Kulathila R]] |
| - | [[Category: Xie, X]] | + | [[Category: Xie X]] |
| - | [[Category: Inhibitor]]
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| - | [[Category: Isocitrate dehydrogenase]]
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| - | [[Category: Mitochondrial]]
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| - | [[Category: Nadph]]
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| - | [[Category: Oxidoreductase]]
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