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==Crystal structure of heterodimeric R132H mutant of human cytosolic NADP(+)-dependent isocitrate dehydrogenase in complex with NADP and isocitrate== | |||
<StructureSection load='3mas' size='340' side='right'caption='[[3mas]], [[Resolution|resolution]] 3.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3mas]] 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=3MAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3MAS 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]] 3.2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ICT:ISOCITRIC+ACID'>ICT</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=3mas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mas OCA], [https://pdbe.org/3mas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3mas RCSB], [https://www.ebi.ac.uk/pdbsum/3mas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3mas 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 == | |||
Human cytosolic NADP-IDH (IDH1) has recently been found to be involved in tumorigenesis. Notably, the tumor-derived IDH1 mutations identified so far mainly occur at Arg132, and mutation R132H is the most prevalent one. This mutation impairs the oxidative IDH activity of the enzyme, but renders a new reduction function of converting alpha-ketoglutarate (alphaKG) to 2-hydroxyglutarate. Here, we report the structures of the R132H mutant IDH1 with and without isocitrate (ICT) bound. The structural data together with mutagenesis and biochemical data reveal a previously undefined initial ICT-binding state and demonstrate that IDH activity requires a conformational change to a closed pre-transition state. Arg132 plays multiple functional roles in the catalytic reaction; in particular, the R132H mutation hinders the conformational changes from the initial ICT-binding state to the pre-transition state, leading to the impairment of the IDH activity. Our results describe for the first time that there is an intermediate conformation that corresponds to an initial ICT-binding state and that the R132H mutation can trap the enzyme in this conformation, therefore shedding light on the molecular mechanism of the "off switch" of the potentially tumor-suppressive IDH activity. Furthermore, we proved the necessity of Tyr139 for the gained alphaKG reduction activity and propose that Tyr139 may play a vital role by compensating the increased negative charge on the C2 atom of alphaKG during the transfer of a hydride anion from NADPH to alphaKG, which provides new insights into the mechanism of the "on switch" of the hypothetically oncogenic reduction activity of IDH1 by this mutation. | |||
Molecular mechanisms of "off-on switch" of activities of human IDH1 by tumor-associated mutation R132H.,Yang B, Zhong C, Peng Y, Lai Z, Ding J Cell Res. 2010 Nov;20(11):1188-200. Epub 2010 Oct 26. PMID:20975740<ref>PMID:20975740</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3mas" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Isocitrate dehydrogenase 3D structures|Isocitrate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Ding J]] | |||
[[Category: Peng Y]] | |||
[[Category: Yang B]] | |||