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4xrx
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4xrx]] 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=4XRX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XRX FirstGlance]. <br> | <table><tr><td colspan='2'>[[4xrx]] 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=4XRX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XRX FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=42V:5-[(E)-(1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL]PYRIDIN-2(1H)-ONE'>42V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=42V:5-[(E)-(1-METHYL-5-OXO-2-THIOXOIMIDAZOLIDIN-4-YLIDENE)METHYL]PYRIDIN-2(1H)-ONE'>42V</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</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=4xrx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xrx OCA], [https://pdbe.org/4xrx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xrx RCSB], [https://www.ebi.ac.uk/pdbsum/4xrx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xrx ProSAT]</span></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=4xrx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xrx OCA], [https://pdbe.org/4xrx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xrx RCSB], [https://www.ebi.ac.uk/pdbsum/4xrx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xrx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] | [https://www.uniprot.org/uniprot/IDHC_HUMAN IDHC_HUMAN] | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Somatic mutations of isocitrate dehydrogenase 1 (IDH1) at R132 are frequently found in certain cancers such as glioma. With losing the activity of wild-type IDH1, the R132H and R132C mutant proteins can reduce alpha-ketoglutaric acid (alpha-KG) to d-2-hydroxyglutaric acid (D2HG). The resulting high concentration of D2HG inhibits many alpha-KG-dependent dioxygenases, including histone demethylases, to cause broad histone hypermethylation. These aberrant epigenetic changes are responsible for the initiation of these cancers. We report the synthesis, structure-activity relationships, enzyme kinetics, and binding thermodynamics of a novel series of 2-thiohydantoin and related compounds, among which several compounds are potent inhibitors of mutant IDH1 with Ki as low as 420 nM. X-ray crystal structures of IDH1(R132H) in complex with two inhibitors are reported, showing their inhibitor-protein interactions. These compounds can decrease the cellular concentration of D2HG, reduce the levels of histone methylation, and suppress the proliferation of stem-like cancer cells in BT142 glioma with IDH1 R132H mutation. | ||
| - | |||
| - | Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.,Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, Li XN, Song Y J Med Chem. 2015 Sep 10;58(17):6899-908. doi: 10.1021/acs.jmedchem.5b00684. Epub , 2015 Aug 26. PMID:26280302<ref>PMID:26280302</ref> | ||
| - | |||
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4xrx" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] | *[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] | ||
| - | == References == | ||
| - | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Crystal structure of a metabolic reductase with (E)-5-((1-methyl-5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)pyridin-2(1H)-one
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Categories: Homo sapiens | Large Structures | Jiang H | Kogiso M | Li X | Song Y | Wu F | Yao Y | Zheng B | Zhou C
