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==Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd13== | |||
<StructureSection load='6bl1' size='340' side='right' caption='[[6bl1]], [[Resolution|resolution]] 2.02Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6bl1]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BL1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BL1 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DWG:(6aS,7S,9S,10aS)-7-methyl-8-oxo-10a-phenyl-2-(phenylamino)-5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazoline-9-carbonitrile'>DWG</scene>, <scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</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=6bl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bl1 OCA], [http://pdbe.org/6bl1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bl1 RCSB], [http://www.ebi.ac.uk/pdbsum/6bl1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bl1 ProSAT]</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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive ,-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design. | |||
Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.,Jakob CG, Upadhyay AK, Donner PL, Nicholl E, Addo SN, Qiu W, Ling C, Gopalakrishnan SM, Torrent M, Cepa SP, Shanley J, Shoemaker AR, Sun CC, Vasudevan A, Woller KR, Shotwell JB, Shaw B, Bian Z, Hutti JE J Med Chem. 2018 Jul 13. doi: 10.1021/acs.jmedchem.8b00305. PMID:30004704<ref>PMID:30004704</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6bl1" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Jakob, C G]] | |||
[[Category: Qiu, W]] | |||
[[Category: Dehydrogenase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Oxidoreductase-oxidoreductase inhibitor complex]] | |||
Revision as of 10:13, 25 July 2018
Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd13Novel Modes of Inhibition of Wild-Type IDH1: Direct Covalent Modification of His315 with Cmpd13
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. Publication Abstract from PubMedIDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive ,-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design. Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.,Jakob CG, Upadhyay AK, Donner PL, Nicholl E, Addo SN, Qiu W, Ling C, Gopalakrishnan SM, Torrent M, Cepa SP, Shanley J, Shoemaker AR, Sun CC, Vasudevan A, Woller KR, Shotwell JB, Shaw B, Bian Z, Hutti JE J Med Chem. 2018 Jul 13. doi: 10.1021/acs.jmedchem.8b00305. PMID:30004704[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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