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| | ==IDH1 R132H in complex with cpd 1== | | ==IDH1 R132H in complex with cpd 1== |
| - | <StructureSection load='4umx' size='340' side='right' caption='[[4umx]], [[Resolution|resolution]] 1.88Å' scene=''> | + | <StructureSection load='4umx' size='340' side='right'caption='[[4umx]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4umx]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UMX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UMX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4umx]] 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=4UMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UMX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=VVS:2,6-BIS(1H-IMIDAZOL-1-YLMETHYL)-4-(2,4,4-TRIMETHYLPENTAN-2-YL)PHENOL'>VVS</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]] 1.88Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4umy|4umy]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=VVS:2,6-BIS(1H-IMIDAZOL-1-YLMETHYL)-4-(2,4,4-TRIMETHYLPENTAN-2-YL)PHENOL'>VVS</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=4umx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umx OCA], [https://pdbe.org/4umx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4umx RCSB], [https://www.ebi.ac.uk/pdbsum/4umx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4umx 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=4umx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umx RCSB], [http://www.ebi.ac.uk/pdbsum/4umx PDBsum]</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 == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4umx" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Marquette, J P]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Mathieu, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Isocitrate dehydrogenase inhibitor]] | + | [[Category: Marquette JP]] |
| - | [[Category: Oxidoreductase]] | + | [[Category: Mathieu M]] |
| Structural highlights
Disease
IDHC_HUMAN Defects in IDH1 are involved in the development of glioma (GLM) [MIM: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
IDHC_HUMAN
Publication Abstract from PubMed
Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) confer a neomorphic enzymatic activity: the reduction of alpha-ketoglutarate (alphaKG) to D-2-hydroxyglutaric acid (2HG), which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. While selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well-understood. A high-throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified Compound 1, a bis-imidazole phenol that inhibits 2HG production in cells. We investigated the mode of inhibition of Compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site, and that inhibition is competitive with respect to Mg2+. A crystal structure of Compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes a direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1, and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme.
Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule.,Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, He T, Shi C, Bedel O, McLean LR, Le-Strat F, Zhang Y, Marquette JP, Gao Q, Zhang B, Rak A, Hoffmann D, Rooney E, Vassort A, Englaro W, Li Y, Patel V, Adrian F, Gross S, Wiederschain D, Cheng H, Licht S J Biol Chem. 2014 Nov 12. pii: jbc.M114.608497. PMID:25391653[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, He T, Shi C, Bedel O, McLean LR, Le-Strat F, Zhang Y, Marquette JP, Gao Q, Zhang B, Rak A, Hoffmann D, Rooney E, Vassort A, Englaro W, Li Y, Patel V, Adrian F, Gross S, Wiederschain D, Cheng H, Licht S. Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule. J Biol Chem. 2014 Nov 12. pii: jbc.M114.608497. PMID:25391653 doi:http://dx.doi.org/10.1074/jbc.M114.608497
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