4i3l: Difference between revisions
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==Crystal structure of a metabolic reductase with 6-benzyl-1-hydroxy-4-methylpyridin-2(1H)-one== | |||
<StructureSection load='4i3l' size='340' side='right' caption='[[4i3l]], [[Resolution|resolution]] 3.29Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4i3l]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I3L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I3L FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BZ:6-BENZYL-1-HYDROXY-4-METHYLPYRIDIN-2(1H)-ONE'>1BZ</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3map|3map]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IDH1, PICD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4i3l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i3l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i3l RCSB], [http://www.ebi.ac.uk/pdbsum/4i3l PDBsum]</span></td></tr> | |||
</table> | |||
== 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. | |||
== Function == | |||
== | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | |||
Mutations in isocitrate dehydrogenase (IDH), a key enzyme in the tricarboxylic acid cycle, have recently been found in ~75% glioma and ~20% acute myeloid leukemia. Different from the wild-type enzyme, mutant IDH1 catalyzes the reduction of alpha-ketoglutaric acid to D-2-hydroxyglutaric acid. Strong evidence has shown mutant IDH1 represents a novel target for this type of cancer. We found two 1-hydroxypyridin-2-one compounds that are potent inhibitors of R132H and R132C IDH1 mutants with Ki values as low as 120 nM. These compounds exhibit >60-fold selectivity against wild-type IDH1 and can inhibit the production of D-2-hydroxyglutaric acid in IDH1 mutated cells, representing novel chemical probes for cancer biology studies. We also report the first inhibitor-bound crystal structures of IDH1(R132H), showing these inhibitors have H-bond, electrostatic and hydrophobic interactions with the mutant enzyme. Comparison with the substrate-bound IDH1 structures revealed the structural basis for the high enzyme selectivity of these compounds. | |||
Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase.,Zheng B, Yao Y, Liu Z, Deng L, Anglin JL, Jiang H, Prasad BV, Song Y ACS Med Chem Lett. 2013 Jun 13;4(6):542-546. PMID:23795241<ref>PMID:23795241</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Isocitrate dehydrogenase|Isocitrate dehydrogenase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Anglin, J L | [[Category: Anglin, J L]] | ||
[[Category: Deng, L | [[Category: Deng, L]] | ||
[[Category: Jiang, H | [[Category: Jiang, H]] | ||
[[Category: Liu, Z | [[Category: Liu, Z]] | ||
[[Category: Prasad, B V.V | [[Category: Prasad, B V.V]] | ||
[[Category: Song, Y | [[Category: Song, Y]] | ||
[[Category: Yao, Y | [[Category: Yao, Y]] | ||
[[Category: Zheng, B | [[Category: Zheng, B]] | ||
[[Category: Isocitrate dehydrogenase]] | [[Category: Isocitrate dehydrogenase]] | ||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | [[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | ||
