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| | ==Crystal Structures of IDH2 R140Q in complex with AG-881== | | ==Crystal Structures of IDH2 R140Q in complex with AG-881== |
| - | <StructureSection load='6adi' size='340' side='right' caption='[[6adi]], [[Resolution|resolution]] 1.97Å' scene=''> | + | <StructureSection load='6adi' size='340' side='right'caption='[[6adi]], [[Resolution|resolution]] 1.97Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6adi]] 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=6ADI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ADI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6adi]] 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=6ADI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ADI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9UO:6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine'>9UO</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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]] 1.969Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9UO:6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine'>9UO</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6adi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6adi OCA], [https://pdbe.org/6adi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6adi RCSB], [https://www.ebi.ac.uk/pdbsum/6adi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6adi 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=6adi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6adi OCA], [http://pdbe.org/6adi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6adi RCSB], [http://www.ebi.ac.uk/pdbsum/6adi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6adi 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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6adi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6adi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ma, R]] | + | [[Category: Large Structures]] |
| - | [[Category: Yun, C H]] | + | [[Category: Ma R]] |
| - | [[Category: Oxidoreductase]] | + | [[Category: Yun CH]] |
| Structural highlights
Disease
IDHP_HUMAN D-2-hydroxyglutaric aciduria. Defects in IDH2 are the cause of D-2-hydroxyglutaric aciduria type 2 (D2HGA2) [MIM: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.[1]
Function
IDHP_HUMAN Plays a role in intermediary metabolism and energy production. It may tightly associate or interact with the pyruvate dehydrogenase complex.
Publication Abstract from PubMed
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (alpha-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2.,Ma R, Yun CH Biochem Biophys Res Commun. 2018 Aug 18. pii: S0006-291X(18)31750-9. doi:, 10.1016/j.bbrc.2018.08.068. PMID:30131249[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kranendijk M, Struys EA, van Schaftingen E, Gibson KM, Kanhai WA, van der Knaap MS, Amiel J, Buist NR, Das AM, de Klerk JB, Feigenbaum AS, Grange DK, Hofstede FC, Holme E, Kirk EP, Korman SH, Morava E, Morris A, Smeitink J, Sukhai RN, Vallance H, Jakobs C, Salomons GS. IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science. 2010 Oct 15;330(6002):336. doi: 10.1126/science.1192632. Epub 2010 Sep, 16. PMID:20847235 doi:http://dx.doi.org/10.1126/science.1192632
- ↑ Ma R, Yun CH. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem Biophys Res Commun. 2018 Aug 18. pii: S0006-291X(18)31750-9. doi:, 10.1016/j.bbrc.2018.08.068. PMID:30131249 doi:http://dx.doi.org/10.1016/j.bbrc.2018.08.068
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