6vei

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<StructureSection load='6vei' size='340' side='right'caption='[[6vei]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='6vei' size='340' side='right'caption='[[6vei]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6vei]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VEI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6VEI FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6vei]] 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=6VEI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6VEI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33O:3,6,9,12,15,18,21,24,27,30,33,36-DODECAOXAOCTATRIACONTANE-1,38-DIOL'>33O</scene>, <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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MLA:MALONIC+ACID'>MLA</scene>, <scene name='pdbligand=MLT:D-MALATE'>MLT</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=33O:3,6,9,12,15,18,21,24,27,30,33,36-DODECAOXAOCTATRIACONTANE-1,38-DIOL'>33O</scene>, <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=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MLA:MALONIC+ACID'>MLA</scene>, <scene name='pdbligand=MLT:D-MALATE'>MLT</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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">[[6vfz|6vfz]], [[6vg0|6vg0]]</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6vfz|6vfz]], [[6vg0|6vg0]]</td></tr>
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<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 HUMAN])</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='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=6vei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vei OCA], [http://pdbe.org/6vei PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vei RCSB], [http://www.ebi.ac.uk/pdbsum/6vei PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vei 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=6vei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vei OCA], [http://pdbe.org/6vei PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vei RCSB], [http://www.ebi.ac.uk/pdbsum/6vei PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vei ProSAT]</span></td></tr>
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== 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.
[[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by &gt;97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.
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Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual Inhibitor of Mutant IDH1 and 2 for Treatment of Glioma.,Konteatis Z, Artin E, Nicolay B, Straley K, Padyana AK, Jin L, Chen Y, Narayaraswamy R, Tong S, Wang F, Zhou D, Cui D, Cai Z, Luo Z, Fang C, Tang H, Lv X, Nagaraja R, Yang H, Su SM, Sui Z, Dang L, Yen K, Popovici-Muller J, Codega P, Campos C, Mellinghoff IK, Biller SA ACS Med Chem Lett. 2020 Jan 22;11(2):101-107. doi:, 10.1021/acsmedchemlett.9b00509. eCollection 2020 Feb 13. PMID:32071674<ref>PMID:32071674</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6vei" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Jin, L]]
[[Category: Jin, L]]

Revision as of 07:23, 4 March 2020

Crystal Structure of Human Cytosolic Isocitrate Dehydrogenase (IDH1) R132H Mutant in Complex with NADPH and AG-881 (Vorasidenib) Inhibitor

PDB ID 6vei

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