9b81
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of wild type IDH1 bound to compound 4== | |
| + | <StructureSection load='9b81' size='340' side='right'caption='[[9b81]], [[Resolution|resolution]] 2.56Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9b81]] 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=9B81 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9B81 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.56Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AI4:2-methyl-2-(6-{4-[(2S)-1,1,1-trifluoro-2-hydroxypropan-2-yl]benzoyl}-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl)propanenitrile'>A1AI4</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></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=9b81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9b81 OCA], [https://pdbe.org/9b81 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9b81 RCSB], [https://www.ebi.ac.uk/pdbsum/9b81 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9b81 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [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;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate. | ||
| - | + | Biostructural, biochemical and biophysical studies of mutant IDH1.,McCoy MA, Lu J, Richard Miller F, Soisson SM, Lam MH, Fischer C Nat Commun. 2024 Sep 9;15(1):7877. doi: 10.1038/s41467-024-51692-0. PMID:39251618<ref>PMID:39251618</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 9b81" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| + | [[Category: Large Structures]] | ||
| + | [[Category: Abeywickrema P]] | ||
| + | [[Category: Heo MR]] | ||
| + | [[Category: Lu J]] | ||
| + | [[Category: McCoy M]] | ||
| + | [[Category: Parthasarathy G]] | ||
| + | [[Category: Soisson SM]] | ||
Current revision
Crystal structure of wild type IDH1 bound to compound 4
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