5l58

<StructureSection load='5l58' size='340' side='right' caption='[[5l58]], [[Resolution|resolution]] 3.04&Aring;' scene=''>

<table><tr><td colspan='2'>[[5l58]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L58 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L58 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6MX:2-[(3~{R})-1-[6-CYCLOHEXYLSULFANYL-5-[[(1~{R},3~{S})-5-OXIDANYL-2-ADAMANTYL]CARBAMOYL]PYRIDIN-2-YL]PYRROLIDIN-3-YL]ETHANOIC+ACID'>6MX</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5l58 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l58 OCA], [http://pdbe.org/5l58 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l58 RCSB], [http://www.ebi.ac.uk/pdbsum/5l58 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l58 ProSAT]</span></td></tr>

[[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.

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== Publication Abstract from PubMed ==

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

 

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== References ==

[[Category: Levy, C]]

[[Category: Allosteric]]

[[Category: Iso-citrate dehydrogenase]]

[[Category: Oxidoreductase]]